Antibacterial Compounds

ABSTRACT

The present invention relates to the following compounds 
     
       
         
         
             
             
         
       
     
     wherein the integers are as defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of tuberculosis.

The present invention relates to novel compounds. The invention alsorelates to such compounds for use as a pharmaceutical and further forthe use in the treatment of bacterial diseases, including diseasescaused by pathogenic mycobacteria such as Mycobacterium tuberculosis.Such compounds may work by interfering with ATP synthase in M.tuberculosis, with the inhibition of cytochrome bc₁ activity as theprimary mode of action. Hence, primarily, such compounds areantitubercular agents.

BACKGROUND OF THE INVENTION

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB),a serious and potentially fatal infection with a world-widedistribution. Estimates from the World Health Organization indicate thatmore than 8 million people contract TB each year, and 2 million peopledie from tuberculosis yearly. In the last decade, TB cases have grown20% worldwide with the highest burden in the most impoverishedcommunities. If these trends continue, TB incidence will increase by 41%in the next twenty years. Fifty years since the introduction of aneffective chemotherapy, TB remains after AIDS, the leading infectiouscause of adult mortality in the world. Complicating the TB epidemic isthe rising tide of multi-drug-resistant strains, and the deadlysymbiosis with HIV. People who are HIV-positive and infected with TB are30 times more likely to develop active TB than people who areHIV-negative and TB is responsible for the death of one out of everythree people with HIV/AIDS worldwide

Existing approaches to treatment of tuberculosis all involve thecombination of multiple agents. For example, the regimen recommended bythe U.S. Public Health Service is a combination of isoniazid, rifampicinand pyrazinamide for two months, followed by isoniazid and rifampicinalone for a further four months. These drugs are continued for a furtherseven months in patients infected with HIV. For patients infected withmulti-drug resistant strains of M. tuberculosis, agents such asethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide,cycloserine, ciprofoxacin and ofloxacin are added to the combinationtherapies. There exists no single agent that is effective in theclinical treatment of tuberculosis, nor any combination of agents thatoffers the possibility of therapy of less than six months' duration.

There is a high medical need for new drugs that improve currenttreatment by enabling regimens that facilitate patient and providercompliance. Shorter regimens and those that require less supervision arethe best way to achieve this. Most of the benefit from treatment comesin the first 2 months, during the intensive, or bactericidal, phase whenfour drugs are given together; the bacterial burden is greatly reduced,and patients become noninfectious. The 4- to 6-month continuation, orsterilizing, phase is required to eliminate persisting bacilli and tominimize the risk of relapse. A potent sterilizing drug that shortenstreatment to 2 months or less would be extremely beneficial. Drugs thatfacilitate compliance by requiring less intensive supervision also areneeded. Obviously, a compound that reduces both the total length oftreatment and the frequency of drug administration would provide thegreatest benefit.

Complicating the TB epidemic is the increasing incidence ofmulti-drug-resistant strains or MDR-TB. Up to four percent of all casesworldwide are considered MDR-TB—those resistant to the most effectivedrugs of the four-drug standard, isoniazid and rifampin. MDR-TB islethal when untreated and cannot be adequately treated through thestandard therapy, so treatment requires up to 2 years of “second-line”drugs. These drugs are often toxic, expensive and marginally effective.In the absence of an effective therapy, infectious MDR-TB patientscontinue to spread the disease, producing new infections with MDR-TBstrains. There is a high medical need for a new drug with a newmechanism of action, which is likely to demonstrate activity againstdrug resistant, in particular MDR strains.

The term “drug resistant” as used hereinbefore or hereinafter is a termwell understood by the person skilled in microbiology. A drug resistantMycobacterium is a Mycobacterium which is no longer susceptible to atleast one previously effective drug; which has developed the ability towithstand antibiotic attack by at least one previously effective drug. Adrug resistant strain may relay that ability to withstand to itsprogeny. Said resistance may be due to random genetic mutations in thebacterial cell that alters its sensitivity to a single drug or todifferent drugs.

MDR tuberculosis is a specific form of drug resistant tuberculosis dueto a bacterium resistant to at least isoniazid and rifampicin (with orwithout resistance to other drugs), which are at present the two mostpowerful anti-TB drugs. Thus, whenever used hereinbefore or hereinafter“drug resistant” includes multi drug resistant.

Another factor in the control of the TB epidemic is the problem oflatent TB. In spite of decades of tuberculosis (TB) control programs,about 2 billion people are infected by M. tuberculosis, thoughasymptomatically. About 10% of these individuals are at risk ofdeveloping active TB during their lifespan. The global epidemic of TB isfuelled by infection of HIV patients with TB and rise of multi-drugresistant TB strains (MDR-TB). The reactivation of latent TB is a highrisk factor for disease development and accounts for 32% deaths in HIVinfected individuals. To control TB epidemic, the need is to discovernew drugs that can kill dormant or latent bacilli. The dormant TB canget reactivated to cause disease by several factors like suppression ofhost immunity by use of immunosuppressive agents like antibodies againsttumor necrosis factor α or interferon-γ. In case of HIV positivepatients the only prophylactic treatment available for latent TB istwo-three months regimens of rifampicin, pyrazinamide. The efficacy ofthe treatment regime is still not clear and furthermore the length ofthe treatments is an important constrain in resource-limitedenvironments. Hence there is a drastic need to identify new drugs, whichcan act as chemoprophylatic agents for individuals harboring latent TBbacilli.

The tubercle bacilli enter healthy individuals by inhalation; they arephagocytosed by the alveolar macrophages of the lungs. This leads topotent immune response and formation of granulomas, which consist ofmacrophages infected with M. tuberculosis surrounded by T cells. After aperiod of 6-8 weeks the host immune response cause death of infectedcells by necrosis and accumulation of caseous material with certainextracellular bacilli, surrounded by macrophages, epitheloid cells andlayers of lymphoid tissue at the periphery. In case of healthyindividuals, most of the mycobacteria are killed in these environmentsbut a small proportion of bacilli still survive and are thought to existin a non-replicating, hypometabolic state and are tolerant to killing byanti-TB drugs like isoniazid. These bacilli can remain in the alteredphysiological environments even for individual's lifetime withoutshowing any clinical symptoms of disease. However, in 10% of the casesthese latent bacilli may reactivate to cause disease. One of thehypothesis about development of these persistent bacteria ispatho-physiological environment in human lesions namely, reduced oxygentension, nutrient limitation, and acidic pH. These factors have beenpostulated to render these bacteria phenotypically tolerant to majoranti-mycobacterial drugs.

In addition to the management of the TB epidemic, there is the emergingproblem of resistance to first-line antibiotic agents. Some importantexamples include penicillin-resistant Streptococcus pneumoniae,vancomycin-resistant enterococci, methicillin-resistant Staphylococcusaureus, multi-resistant salmonellae.

The consequences of resistance to antibiotic agents are severe.Infections caused by resistant microbes fail to respond to treatment,resulting in prolonged illness and greater risk of death. Treatmentfailures also lead to longer periods of infectivity, which increase thenumbers of infected people moving in the community and thus exposing thegeneral population to the risk of contracting a resistant straininfection.

Hospitals are a critical component of the antimicrobial resistanceproblem worldwide. The combination of highly susceptible patients,intensive and prolonged antimicrobial use, and cross-infection hasresulted in infections with highly resistant bacterial pathogens.

Self-medication with antimicrobials is another major factor contributingto resistance. Self-medicated antimicrobials may be unnecessary, areoften inadequately dosed, or may not contain adequate amounts of activedrug.

Patient compliance with recommended treatment is another major problem.Patients forget to take medication, interrupt their treatment when theybegin to feel better, or may be unable to afford a full course, therebycreating an ideal environment for microbes to adapt rather than bekilled.

Because of the emerging resistance to multiple antibiotics, physiciansare confronted with infections for which there is no effective therapy.The morbidity, mortality, and financial costs of such infections imposean increasing burden for health care systems worldwide.

Therefore, there is a high need for new compounds to treat bacterialinfections, especially mycobacterial infections including drug resistantand latent mycobacterial infections, and also other bacterial infectionsespecially those caused by resistant bacterial strains.

Anti-infective compounds for treating tuberculosis have been disclosedin e.g. international patent application WO 2011/113606. Such a documentis concerned with compounds that would prevent M. tuberculosismultiplication inside the host macrophage and relates to compounds witha bicyclic core, imidazopyridines, which are linked (e.g. via an amidomoiety) to e.g. an optionally substituted benzyl group.

International patent application WO 2014/015167 also discloses compoundsthat are disclosed as being of potential use in the treatment oftuberculosis. Such compounds disclosed herein have a bicycle (a5,5-fused bicycle) as an essential element, which is substituted by alinker group (e.g. an amido group), which itself may be attached toanother bicycle or aromatic group. Such compounds in this document donot contain a series of more than three rings.

Journal article Nature Medicine, 19, 1157-1160 (2013) by Pethe et al“Discovery of Q203, a potent clinical candidate for the treatment oftuberculosis” identifies a specific compound that was tested against M.tuberculosis. This compound Q203 is depicted below.

This clinical candidates is also discussed in journal article, J.Medicinal Chemistry, 2014, 57 (12), pp 5293-5305. It is stated to haveactivity against MDR tuberculosis, and have activity against the strainM. tuberculosis H37Rv at a MIC₅₀ of 0.28 nM inside macrophages. Positivecontrol data (using known anti-TB compounds bedaquiline, isoniazid andmoxifloxacin) are also reported. This document also suggests a mode ofaction, based on studies with mutants. It postulates that it acts byinterfering with ATP synthase in M. tuberculosis, and that theinhibition of cytochrome bc₁ activity is the primary mode of action.Cytochrome bc₁ is an essential component of the electron transport chainrequired for ATP synthesis. It appeared that Q203 was highly activeagainst both replicating and non-replicating bacteria

International patent application WO 2015/014993 also discloses compoundsas having activity against M. tuberculosis. International patentapplications WO 2013/033070 and WO 2013/033167 disclose variouscompounds as kinase modulators.

The purpose of the present invention is to provide compounds for use inthe treatment of bacterial diseases, particularly those diseases causedby pathogenic bacteria such as Mycobacterium tuberculosis (including thelatent disease and including drug resistant M. tuberculosis strains).Such compounds may also be novel and may act by interfering with ATPsynthase in M. tuberculosis, with the inhibition of cytochrome bc₁activity being considered the primary mode of action.

SUMMARY OF THE INVENTION

There is now provided a compound of formula (I) for use in the treatmentof tuberculosis

whereinR¹ represents C₁₋₆ alkyl or hydrogen;L¹ represents a linker group —C(R^(a))(R^(b))— (or is not present);Het represents a heteroaromatic linker group (which linker group mayitself be optionally substituted by one or more substituents selectedfrom fluoro, —O—R andC₁₋₆ alkyl, wherein the latter alkyl moiety is itself optionallysubstituted by one or more fluoro atoms);R^(a), R^(b) and R^(c) independently represent hydrogen or C₁₋₆ alkyl(optionally substituted by one or more fluoro atoms);X¹ represents —N(R²)(R³);R² and R³:

-   -   (i) independently represent hydrogen or, preferably, C₁₋₆ alkyl        optionally substituted by one or more substituents selected from        Q¹ and ═O;    -   (ii) independently represent aryl or heteroaryl, each of which        is optionally substituted by one or more substituents selected        from Q²;    -   (iii) independently represent cycloalkyl or heterocycloalkyl,        each of which is optionally substituted by one or more        substituents selected from Q³ and ═O; or    -   (iv) can be linked together to form:        -   a. a 3- to 8-membered ring optionally containing one to            three heteroatoms (e.g. nitrogen, oxygen and/or sulfur), and            which ring is optionally substituted by one or more            substituents selected from Q⁴ and ═O;        -   b. a “fused” bicyclic ring of the following type:

-   -   -   c. a “spiro” ring of the following type:

Q¹, Q², Q³, Q⁴ and Q⁵ each independently represent one or moresubstituents selected from halo, C₁₋₆ alkyl, —OC₁₋₆ alkyl (which lattertwo alkyl moieties may themselves be optionally substituted by one ormore halo, e.g. fluoro, atoms), aryl and heteroaryl (which latter twoaromatic groups may themselves be optionally substituted by one or moresubstituents selected from halo, C₁₋₆ alkyl and —OC₁₋₆ alkyl, whichlatter two alkyl moieties may themselves be substituted with one or morefluoro atoms);n1 and n2 independently represent 0 or 1 (hence, the X^(a)-containingring may be 3-, 4- or 5-membered, or (when m is 2), 6-membered);X^(a) represents —C(R^(a1))(R^(b1))_(m)— or —N(R^(c1))—;m represents 1 or 2;each R^(a1) and R^(b1) independently represents fluoro, hydrogen or C₁₋₆alkyl;R^(c1) represents hydrogen or C₁₋₆ alkyl;X^(b) represents C(R^(d)), N, O (in which case L² is not present) or C═O(in which case L² is also not present);R^(d) represents H, F or —OR^(e) (wherein R^(e) represents H or C₁₋₆alkyl optionally substituted by one or more fluoro atoms);q¹ represents —X^(c)—(CH₂)_(n1)—X^(d)—;n1 represents 0, 1 or 2;q² represents —X^(e)—(CH₂)_(n2)—X^(f)—;n2 represents 0, 1 or 2, but wherein n1 and n2 do not both represent 0;X^(c) (which is attached to X^(a)) is either not present, or, when X^(a)represents CH, then X^(c) may represent —O—, —NH— or —S—;X^(d) is either not present, or, when n1 represents 2 or when X^(c) isnot present, X^(a) represents C(R^(c)) and n1 represents 1, then X^(d)may also represent —O—, —NH— or —S—;X^(e) and X^(f) independently are either not present, or mayindependently represent —O—, —NH— or —S—, provided that theaforementioned heteroatoms are not directly attached to or α to anotherheteroatom;q³ represents —X^(g)—(CH₂)_(n3)—X^(h)—;q⁴ represents —X^(i)—(CH₂)_(n4)—X^(j)—;n3 represents 0, 1 or 2;n4 represents 0, 1 or 2, but wherein n3 and n4 do not both represent 0;X^(g), X^(h), X^(i) and X^(j) independently are either not present, ormay represent —O—, —NH— or —S—, provided that the aforementionedheteroatoms are not directly attached to or α to another heteroatom;when X^(b) represents O or C═O, then L² is not present;when X^(b) represents C(R^(d)) (e.g. CH) or N, then L² may representhydrogen, halo, —OR^(f), —C(O)—R^(g), C₁₋₆ alkyl (optionally substitutedby one or more halo, e.g. fluoro atoms) or an aromatic group (optionallysubstituted by one or more substituents selected from halo, C₁₋₆ alkyl(itself optionally substituted by one or more substituents selected fromfluoro, —CF₃ and/or —SF₅), —OC₁₋₆alkyl (itself optionally substituted byone or more fluoro atoms), —O— phenyl (itself optionally substituted byhalo, C₁₋₆alkyl,C₁₋₆fluoroalkyl and/or —OC₁₋₆alkyl) or —SF₅);R^(f) represents hydrogen, C₁₋₆ alkyl (optionally substituted by one ormore fluoro) or an aromatic group (itself optionally substituted by oneor more substituents selected from halo, C₁₋₆alkyl and —OC₁₋₆alkyl,where the latter two alkyl moieties may themseleves be optionallysubstituted by one or more fluoro atoms);R^(g) represents hydrogen or C₁₋₆alkyl (optionally substituted by one ormore substituents selected from fluoro, or —OC₁₋₃ alkyl, which lattermoiety is also optionally substituted by one or more fluoro atoms) or anaromatic group (optionally substituted by one or more substituentsselected from halo, C₁₋₆ alkyl or —OC₁₋₆alkyl);ring A is a 5-membered aromatic ring containing at least one heteroatom(preferably containing at least one nitrogen atom);ring B is a 5- or 6-membered ring, which may be aromatic ornon-aromatic, optionally containing one to four heteroatoms (preferablyselected from nitrogen, oxygen and sulfur);either ring A and/or ring B may be optionally substituted by one or moresubstituents selected from: halo, C₁₋₆ alkyl (optionally substituted byone or more halo, e.g. fluoro atoms) and/or —OC₁₋₆alkyl (itselfoptionally substituted by one or more fluoro atoms),or a pharmaceutically-acceptable salt thereof,which compounds may be referred to herein as “compounds of theinvention”.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound offormula I with one or more equivalents of an appropriate acid or base,optionally in a solvent, or in a medium in which the salt is insoluble,followed by removal of said solvent, or said medium, using standardtechniques (e.g. in vacuo, by freeze-drying or by filtration). Salts mayalso be prepared by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms that the compounds of formula (I) are able toform. These pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

For the purposes of this invention solvates, prodrugs, N-oxides andstereoisomers of compounds of the invention are also included within thescope of the invention.

The term “prodrug” of a relevant compound of the invention includes anycompound that, following oral or parenteral administration, ismetabolised in vivo to form that compound in anexperimentally-detectable amount, and within a predetermined time (e.g.within a dosing interval of between 6 and 24 hours (i.e. once to fourtimes daily)). For the avoidance of doubt, the term “parenteral”administration includes all forms of administration other than oraladministration.

Prodrugs of compounds of the invention may be prepared by modifyingfunctional groups present on the compound in such a way that themodifications are cleaved, in vivo when such prodrug is administered toa mammalian subject. The modifications typically are achieved bysynthesising the parent compound with a prodrug substituent. Prodrugsinclude compounds of the invention wherein a hydroxyl, amino,sulfhydryl, carboxy or carbonyl group in a compound of the invention isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxy functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elesevier, New York-Oxford (1985).

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. Positional isomers may also be embraced by the compounds ofthe invention. All such isomers (e.g. if a compound of the inventionincorporates a double bond or a fused ring, the cis- and trans-forms,are embraced) and mixtures thereof are included within the scope of theinvention (e.g. single positional isomers and mixtures of positionalisomers may be included within the scope of the invention).

Compounds of the invention may also exhibit tautomerism. All tautomericforms (or tautomers) and mixtures thereof are included within the scopeof the invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerisations. Valencetautomers include interconversions by reorganisation of some of thebonding electrons.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person.

All stereoisomers (including but not limited to diastereoisomers,enantiomers and atropisomers) and mixtures thereof (e.g. racemicmixtures) are included within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention.Exemplary isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I.Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and for substratetissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) isotopesare useful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances. Positronemitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positronemission tomography (PET) studies to examine substrate receptoroccupancy. Isotopically labeled compounds of the present invention cangenerally be prepared by following procedures analogous to thosedisclosed in the Scheme 1 and/or in the Examples herein below, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkyl group). Such cycloalkyl groups may be monocyclic orbicyclic and may further be bridged. Further, when there is a sufficientnumber (i.e. a minimum of four) of carbon atoms, such groups may also bepart cyclic. Such alkyl groups may also be saturated or, when there is asufficient number (i.e. a minimum of two) of carbon atoms, beunsaturated (forming, for example, a C_(2-q) alkenyl or a C_(2-q)alkynyl group).

C_(3-q) cycloalkyl groups (where q is the upper limit of the range) thatmay be specifically mentioned may be monocyclic or bicyclic alkylgroups, which cycloalkyl groups may further be bridged (so forming, forexample, fused ring systems such as three fused cycloalkyl groups). Suchcycloalkyl groups may be saturated or unsaturated containing one or moredouble bonds (forming for example a cycloalkenyl group). Substituentsmay be attached at any point on the cycloalkyl group. Further, wherethere is a sufficient number (i.e. a minimum of four) such cycloalkylgroups may also be part cyclic.

The term “halo”, when used herein, preferably includes fluoro, chloro,bromo and iodo.

Heterocyclic groups when referred to herein may include aromatic ornon-aromatic heterocyclic groups, and hence encompass heterocycloalkyland hetereoaryl. Equally, “aromatic or non-aromatic 5- or 6-memberedrings” may be heterocyclic groups (as well as carbocyclic groups) thathave 5- or 6-members in the ring.

Heterocycloalkyl groups that may be mentioned include non-aromaticmonocyclic and bicyclic heterocycloalkyl groups in which at least one(e.g. one to four) of the atoms in the ring system is other than carbon(i.e. a heteroatom), and in which the total number of atoms in the ringsystem is between 3 and 20 (e.g. between three and ten, e.g between 3and 8, such as 5- to 8-). Such heterocycloalkyl groups may also bebridged. Further, such heterocycloalkyl groups may be saturated orunsaturated containing one or more double and/or triple bonds, formingfor example a C_(2-q) heterocycloalkenyl (where q is the upper limit ofthe range) group. C_(2-q) heterocycloalkyl groups that may be mentionedinclude 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl,azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl(including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl,imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl,6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl,piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl,tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl,thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including1,3,5-trithianyl), tropanyl and the like. Substituents onheterocycloalkyl groups may, where appropriate, be located on any atomin the ring system including a heteroatom. The point of attachment ofheterocycloalkyl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heterocycloalkyl groups may also be in the N- or S-oxidisedform. Heterocycloalkyl mentioned herein may be stated to be specificallymonocyclic or bicyclic.

Aryl groups that may be mentioned include C₆₋₂₀, such as C₆₋₁₂ (e.g.C₆₋₁₀) aryl groups. Such groups may be monocyclic, bicyclic or tricyclicand have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which atleast one ring is aromatic. C₆₋₁₀ aryl groups include phenyl, naphthyland the like, such as 1,2,3,4-tetrahydronaphthyl. The point ofattachment of aryl groups may be via any atom of the ring system. Forexample, when the aryl group is polycyclic the point of attachment maybe via atom including an atom of a non-aromatic ring. However, when arylgroups are polycyclic (e.g. bicyclic or tricyclic), they are preferablylinked to the rest of the molecule via an aromatic ring. Most preferredaryl groups that may be mentioned herein are “phenyl”.

Unless otherwise specified, the term “heteroaryl” when used hereinrefers to an aromatic group containing one or more heteroatom(s) (e.g.one to four heteroatoms) preferably selected from N, O and S. Heteroarylgroups include those which have between 5 and 20 members (e.g. between 5and 10) and may be monocyclic, bicyclic or tricyclic, provided that atleast one of the rings is aromatic (so forming, for example, a mono-,bi-, or tricyclic heteroaromatic group). When the heteroaryl group ispolycyclic the point of attachment may be via any atom including an atomof a non-aromatic ring. However, when heteroaryl groups are polycyclic(e.g. bicyclic or tricyclic), they are preferably linked to the rest ofthe molecule via an aromatic ring. Heteroaryl groups that may bementioned include 3,4-dihydro-1H-isoquinolinyl, 1,3-dihydroisoindolyl,1,3-dihydroisoindolyl (e.g. 3,4-dihydro-1H-isoquinolin-2-yl,1,3-dihydroisoindol-2-yl, 1,3-dihydroisoindol-2-yl; i.e. heteroarylgroups that are linked via a non-aromatic ring), or, preferably,acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl(including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl,benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl,benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl(including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl,benzomorpholinyl, benzoselenadiazolyl (including2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl,cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl,indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl,naphthyridinyl (including 1,6-naphthyridinyl or, preferably,1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl,phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl,tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl,thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl,1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents onheteroaryl groups may, where appropriate, be located on any atom in thering system including a heteroatom. The point of attachment ofheteroaryl groups may be via any atom in the ring system including(where appropriate) a heteroatom (such as a nitrogen atom), or an atomon any fused carbocyclic ring that may be present as part of the ringsystem. Heteroaryl groups may also be in the N- or S-oxidised form.Heteroaryl groups mentioned herein may be stated to be specificallymonocyclic or bicyclic. When heteroaryl groups are polycyclic in whichthere is a non-aromatic ring present, then that non-aromatic ring may besubstituted by one or more ═O group. Most preferred heteroaryl groupsthat may be mentioned herein are 5- or 6-membered aromatic groupscontaining 1, 2 or 3 heteroatoms (e.g. preferably selected fromnitrogen, oxygen and sulfur).

It may be specifically stated that the heteroaryl group is monocyclic orbicyclic. In the case where it is specified that the heteroaryl isbicyclic, then it may consist of a five-, six- or seven-memberedmonocyclic ring (e.g. a monocyclic heteroaryl ring) fused with anotherfive-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroarylring).

Heteroatoms that may be mentioned include phosphorus, silicon, boronand, preferably, oxygen, nitrogen and sulfur.

When “aromatic” groups are referred to herein, they may be aryl orheteroaryl. When “aromatic linker groups” are referred to herein, theymay be aryl or heteroaryl, as defined herein, any may be monocyclic orpolycyclic (e.g. bicyclic) and attached to the remainder of the moleculevia any possible atoms of that linker group. However, it mayspecifically be mentioned that the linker group is a heteroaromaticlinker group, in which case such a moiety is aromatic and has to containat least one heteroatom.

For the avoidance of doubt, where it is stated herein that a group maybe substituted by one or more substituents (e.g. selected from C₁₋₆alkyl), then those substituents (e.g. alkyl groups) are independent ofone another. That is, such groups may be substituted with the samesubstituent (e.g. same alkyl substituent) or different (e.g. alkyl)substituents.

For the avoidance of doubt, where Q⁵ is mentioned herein, thisrepresents one or more optional substituents on the bicycle to which itis attached, and such optional substituents may be situated on either(or both) rings of such bicycle (i.e. the N-containing 5-membered ringand/or the X^(a)-containing ring).

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred feature) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation from e.g. a reaction mixture to a usefuldegree of purity.

Compounds of the invention that may be mentioned include in which:

R² and R³:

-   -   (i) independently represent hydrogen or, preferably, C₁₋₆ alkyl        optionally substituted by one or more substituents selected from        Q¹ and ═O;    -   (ii) independently represent aryl or heteroaryl, each of which        is optionally substituted by one or more substituents selected        from Q²;    -   (iii) independently represent cycloalkyl or heterocycloalkyl,        each of which is optionally substituted by one or more        substituents selected from Q³ and ═O; or    -   (iv) can be linked together to form:        -   a. a 3- to 8-membered ring optionally containing one to            three heteroatoms (e.g. nitrogen, oxygen and/or sulfur), and            which ring is optionally substituted by one or more            substituents selected from Q⁴ and ═O;        -   b. a “fused” bicyclic ring of the following type:

-   -   -   c. a “spiro” ring of the following type:

Hence, in an aspect, when R² and R³ are linked together to form a“fused” bicyclic ring, it is of the following type:

i.e. n1 and n2 independently represent 1.

In two different aspects of the invention:

-   -   n1 and n2 both represent 1;    -   n1 and n2 both represent 0.

Certain (e.g. preferred) aspects of compounds of the invention includethose in which:

R^(e) represents hydrogen;R^(d) represents hydrogen;L¹ preferably represents a linker group as defined by —C(R^(a))(R^(b))—;X^(c) (which is attached to X^(a)) is either not present, or, when X^(a)represents CH, then X^(c) may also represent —O—;X^(d) is either not present, or, when n1 represents 2 or when X^(c) isnot present, X^(a) represents C(R^(c)) and n1 represents 1, then X^(d)may also represent —O—;X^(e) and X^(f) independently are either not present, or mayindependently represent —O—, provided that the aforementioned oxygenatom is not directly attached to or a to another heteroatom;when X^(c) and/or X^(d) represent —O—, —NH— or —S—, it is understoodthat such heteroatoms may not be attached directly (or a to) to anotherheteroatom.

More preferred compounds of the invention include those in which:

R¹ represents hydrogen;R^(a) and R^(b) independently represent hydrogen;L¹ represents —CH₂—;when X¹ represents a heteroaromatic linker group (where the point ofattachment may be via any atom of the ring system), then it in a majoraspect of the invention:

-   -   it is a bicyclic heteroaromatic linker group;    -   it is a bicyclic heteroaromatic group linked to L¹ (or the amido        moiety, when L¹ is not present) via a carbocyclic aromatic        moiety, so forming e.g.:

-   -   -   in which “het” (in the above instance) is a heteroaromatic            5- or 6-membered ring;

    -   a fused bicyclic ring system comprising a phenyl and/or a 5- or        6-membered monocyclic heteroaryl group (for instance forming a        9- or 10-membered heteroaromatic group, which consists of two        separate rings fused with each other, in which each ring is 5-        or 6-membered so forming a 6,6- or 6,5- or fused bicyclic ring),        hence including groups such as those described below:        -   quinolylene (such as 2-quinolylene or 3-quinolylene), e.g.:

-   -   -   quinoxalinyl (such as 2-quinolylenp), e.g.:

-   -   such heteroaromatic linker groups may be optionally substituted        by one or more substituents as defined herein. In an aspect, the        heteroaromatic linker group is not substituted or is only        substituted (where possible) on a heteroatom (e.g. on a nitrogen        heteroatom)—in which case it remains unsubstituted on the carbon        atoms. In an aspect, the points of attachment of the linker        group are via distal atoms, for instance atoms that as far apart        as possible (e.g. in a bicycle of 10 members, those atoms in a        2- and 6-position (or 3- and 7-position) but in another aspect,        they are not necessarily the atoms the furthest apart (e.g. in a        10-membered bicycle, the atoms linked to the rest of the        molecule has be the 3- and 6-atoms too).

When X¹ represents —N(R²)(R³), then:

-   -   (i) R² and R³ independently represent C₁₋₃ alkyl (e.g. methyl or        ethyl) optionally substituted by one or more (e.g. one)        substituent(s) selected from Q¹;    -   (ii) R² and R³ are linked together to form:        -   a. a 4- to 6-membered ring optionally containing one further            heteroatom (e.g. so forming a piperidinyl, piperazinyl or            azetidinyl ring), which is optionally (and, in an aspect,            preferably) substituted by one or more (e.g. one or two)            substituents selected from Q⁴ (in one aspect, e.g. when Q⁴            represents an aromatic substituent, then there is only one            Q⁴ substituent present; in another aspect, e.g. when Q⁴            represents a non-aromatic substituent, e.g. fluoro, then one            or two Q⁴ substituents may be present);        -   b. a fused bicyclic ring in which X^(a) represents —CH₂— and            which is optionally substituted (e.g. at the X^(a) position)            by one or more (e.g. one) Q⁵ substituent(s);        -   c. a spiro ring system, in which X^(b) represents CH and L²            is present and as defined herein.            Q¹ represents aryl (e.g. phenyl) optionally substituted by            e.g. —OC₁₋₃alkyl (itself optionally substituted by one or            more fluoro atoms, so forming e.g. a —OCF₃ group);            Q⁴ represents aryl (e.g. phenyl) optionally substituted by            e.g. —OC₁₋₃alkyl (itself optionally substituted by one or            more fluoro atoms, so forming e.g. a —OCF₃ group) or, in            another aspect, Q⁴ represents fluoro (e.g. two fluoro atoms            substituted at the same carbon atom);            Q⁵ represents halo (e.g. fluoro);            X^(c), X^(d), X^(e) and X^(f) are independently not present;            n1 and n2 independently represent 1;            X^(g), X^(h), X^(i) and X^(j) are independently not present;            n3 and n4 independently represent 1;            L² represents a fluoro substituent or, in another aspect, an            aromatic group (e.g. aryl or phenyl) optionally substituted            by one or more (e.g. one) substituent(s) e.g. selected from            e.g. —OC₁₋₃alkyl (itself optionally substituted by one or            more fluoro atoms, so forming e.g. a —OCF₃ group).

It is preferred that compounds of the invention comprise:

ring A, which is an aromatic ring containing at least one to three (e.g.one or two) heteroatoms, preferably contains at least one nitrogen atom;ring B is more preferably also an aromatic ring (e.g. a 5- or especiallya 6-membered aromatic ring), preferably containing at least one nitrogenatom.

It is preferred that Ring A of the compounds of the invention arerepresented as follows:

Other preferred ring A moieties include:

Monocyclic heteroaryl groups that may be mentioned include 5- or6-membered rings containing one to four heteroatoms (preferably selectedfrom nitrogen, oxygen and sulfur). It is preferred that Ring B of thecompounds of the invention are represented as follows:

where “SUB” may be a relevant optional substituent (or more than whenrelevant substituent, where possible) on a carbon atom or, wherepossible, on a heteroatom e.g. on a NH, thus replacing the H.

Other preferred “Ring B” moieties include:

Preferred substituents (when present; e.g such optional substituents maybe absent or there may be one) on ring B include C₁₋₃ alkyl (e.g.methyl) or halo (e.g. bromo or, more preferably, chloro). Otherpreferred substituents on ring B include —OC₁₋₆alkyl (e.g. —OC₁₋₃alkyl,such as —OCH₃).

Preferred substituents (when present; e.g such optional substituents maybe absent or there may be one) on ring B include C₁₋₃ alkyl (e.g.methyl) or halo (e.g. bromo or, more preferably, chloro). Preferredsubstituents (when present; preferably, there may be one or twosubstituents) on ring A include C₁₋₃ alkyl (e.g. methyl or ethyl). WhenL² represents an aromatic group (e.g. phenyl or pyridyl) and such groupsare substituted, preferred substituents include halo and especially—OC₁₋₃ alkyl (e.g. —O-methyl), where the latter is substituted byfluoro, so forming for example a —OCF₃ group.

The combined ring systems, i.e. Ring A and Ring B may be represented asfollows:

where “SUB” represents one or more possible substituents on the bicycle(i.e. on ring A and/or on ring B) and “Sub” represents a possibleoptional substituent on the N atom of the bicycle (unsubstituted in thiscontext would mean “NH”).

Other combined ring A and ring B systems that may be mentioned includethe following:

Certain compounds of the invention are mentioned (e.g. hereinbefore) foruse in the treatment of tuberculosis. Certain of such compoundsmentioned herein may also be novel per se. And certain of such compoundsmentioned herein may be novel as medicaments/pharmaceuticals (or novelas a component of a pharmaceutical composition/formulation). Hence, infurther aspects of the invention, there is provided the followingcompounds per se or following compounds for use aspharmaceuticals/medicaments (in the latter case such compounds may becomponents of a pharmaceutical composition/formulation):

-   -   (I) Compounds of formula (I) as hereinbefore defined and in        which:        -   L¹ represents —CH₂—;        -   Het represents a bicyclic heteroaromatic group linked to L¹            (or the amido moiety, when L¹ is not present) via a            carbocyclic aromatic moiety, so forming e.g.:

-   -   -   in which “het” (in the above instance) is a heteroaromatic            5- or 6-membered ring;        -   when X¹ represents —N(R²)(R³), then:        -   (i) R² and R³ independently represent C₁₋₃ alkyl (e.g.            methyl or ethyl) optionally substituted by one or more (e.g.            one) substituent(s) selected from Q¹ (but wherein when both            R² and R³ represent alkyl, then at least one is substituted            by Q¹ in which Q¹ represents an optionally substituted aryl            group as defined herein);        -   (ii) R² and R³ are linked together to form:            -   a. a 4- to 6-membered ring optionally containing one                further heteroatom (e.g. so forming a piperidinyl,                piperazinyl or azetidinyl ring), which is substituted by                one or two substituents selected from Q⁴ (in which at                least one Q⁴ substituent is present that represents an                optionally substituted aryl group as defined herein);            -   b. a fused bicyclic ring in which X^(a) represents —CH₂—                and which is optionally substituted (e.g. at the X^(a)                position) by one or more (e.g. one) Q⁵ substituent(s);            -   c. a spiro ring system, in which X^(b) represents CH and                L² is present and as defined herein;        -   when Q¹ represents aryl, then it is an optionally            substituted as defined herein (e.g. by one or more            substituents selected from —OC₁₋₃alkyl (itself optionally            substituted by one or more fluoro atoms, so forming e.g. a            —OCF₃ group));        -   when Q⁴ represents aryl, then it is an optionally            substituted phenyl as defined herein (e.g. by one or more            substituents selected from —OC₁₋₃alkyl (itself optionally            substituted by one or more fluoro atoms, so forming e.g. a            —OCF₃ group));        -   when Q⁴ represents a non-aromatic substituent, then it may            represent e.g. fluoro;        -   Q⁵ represents halo (e.g. fluoro);        -   X^(c), X^(d), X^(e) and X^(f) are independently not present;        -   n1 and n2 independently represent 1;        -   X^(g), X^(h), X^(i) and X^(j) are independently not present;        -   n3 and n4 independently represent 1;        -   L² represents an aromatic group (e.g. aryl or phenyl)            optionally substituted by one or more (e.g. one)            substituent(s) e.g. selected from e.g. —OC₁₋₃alkyl (itself            optionally substituted by one or more fluoro atoms, so            forming e.g. a —OCF₃ group);        -   ring A and ring B together represent a 8 or 9-membered            bicyclic ring (ring A is a 5-membered ring and ring B may be            a 5 or 6-membered ring, in which both rings are preferably            aromatic) containing at least one nitrogen atom (and in a            major embodiment, at least one nitrogen atom that is common            to both rings);        -   optional substituents on ring A and ring B are halo, C₁₋₃            alkyl and —OC₁₋₃alkyl; and        -   other integers are as defined herein;

    -   (II) Compounds as hereinbefore defined (e.g. at (I) above) and        further in which the X^(b)-containing rings are represented as        defined herein or more particularly as follows:

-   -    (or any one of the above-mentioned representations); and/or    -   (III) Compounds as hereinbefore defined (e.g. at (I) and/or (II)        above) and further in which the ring A and ring B bicycles are        represented as defined herein or more particularly as follows:

-   -    (or any one of the above-mentioned representations).

In an embodiment (e.g. in aspect (I) mentioned above), R² and R³ mayrepresent either (i) or (ii) mentioned herein. When R² and R³ represent(ii), then they may represent either a, b or c as defined in thesub-definitions (e.g. in aspect (I) above).

Pharmacology

The compounds according to the invention have surprisingly been shown tobe suitable for the treatment of a bacterial infection including amycobacterial infection, particularly those diseases caused bypathogenic mycobacteria such as Mycobacterium tuberculosis (includingthe latent and drug resistant form thereof). The present invention thusalso relates to compounds of the invention as defined hereinabove, foruse as a medicine, in particular for use as a medicine for the treatmentof a bacterial infection including a mycobacterial infection.

Such compounds of the invention may act by interfering with ATP synthasein M. tuberculosis, with the inhibition of cytochrome bc₁ activity beingthe primary mode of action. Cytochrome bc₁ is an essential component ofthe electron transport chain required for ATP synthesis.

Further, the present invention also relates to the use of a compound ofthe invention, as well as any of the pharmaceutical compositions thereofas described hereinafter for the manufacture of a medicament for thetreatment of a bacterial infection including a mycobacterial infection.

Accordingly, in another aspect, the invention provides a method oftreating a patient suffering from, or at risk of, a bacterial infection,including a mycobacterial infection, which comprises administering tothe patient a therapeutically effective amount of a compound orpharmaceutical composition according to the invention.

The compounds of the present invention also show activity againstresistant bacterial strains.

Whenever used hereinbefore or hereinafter, that the compounds can treata bacterial infection it is meant that the compounds can treat aninfection with one or more bacterial strains.

The invention also relates to a composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound according to theinvention. The compounds according to the invention may be formulatedinto various pharmaceutical forms for administration purposes. Asappropriate compositions there may be cited all compositions usuallyemployed for systemically administering drugs. To prepare thepharmaceutical compositions of this invention, an effective amount ofthe particular compound, optionally in addition salt form, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thesepharmaceutical compositions are desirable in unitary dosage formsuitable, in particular, for administration orally or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution.

Injectable suspensions may also be prepared in which case appropriateliquid carriers, suspending agents and the like may be employed. Alsoincluded are solid form preparations which are intended to be converted,shortly before use, to liquid form preparations.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the active ingredient(s), and, from 1 to 99.95% by weight,more preferably from 30 to 99.9% by weight, even more preferably from 50to 99.9% by weight of a pharmaceutically acceptable carrier, allpercentages being based on the total weight of the composition.

The pharmaceutical composition may additionally contain various otheringredients known in the art, for example, a lubricant, stabilisingagent, buffering agent, emulsifying agent, viscosity-regulating agent,surfactant, preservative, flavouring or colorant.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The daily dosage of the compound according to the invention will, ofcourse, vary with the compound employed, the mode of administration, thetreatment desired and the mycobacterial disease indicated. However, ingeneral, satisfactory results will be obtained when the compoundaccording to the invention is administered at a daily dosage notexceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.

Given the fact that the compounds of formula (Ia) or Formula (Ib) areactive against bacterial infections, the present compounds may becombined with other antibacterial agents in order to effectively combatbacterial infections.

Therefore, the present invention also relates to a combination of (a) acompound according to the invention, and (b) one or more otherantibacterial agents.

The present invention also relates to a combination of (a) a compoundaccording to the invention, and (b) one or more other antibacterialagents, for use as a medicine.

The present invention also relates to the use of a combination orpharmaceutical composition as defined directly above for the treatmentof a bacterial infection.

A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount of(a) a compound according to the invention, and (b) one or more otherantibacterial agents, is also comprised by the present invention.

The weight ratio of (a) the compound according to the invention and (b)the other antibacterial agent(s) when given as a combination may bedetermined by the person skilled in the art. Said ratio and the exactdosage and frequency of administration depends on the particularcompound according to the invention and the other antibacterial agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of the invention and another antibacterial agent mayrange from 1/10 to 10/1, more in particular from 1/5 to 5/1, even morein particular from 1/3 to 3/1.

The compounds according to the invention and the one or more otherantibacterial agents may be combined in a single preparation or they maybe formulated in separate preparations so that they can be administeredsimultaneously, separately or sequentially.

Thus, the present invention also relates to a product containing (a) acompound according to the invention, and (b) one or more otherantibacterial agents, as a combined preparation for simultaneous,separate or sequential use in the treatment of a bacterial infection.

The other antibacterial agents which may be combined with the compoundsof the invention are for example antibacterial agents known in the art.For example, the compounds of the invention may be combined withantibacterial agents known to interfere with the respiratory chain ofMycobacterium tuberculosis, including for example direct inhibitors ofthe ATP synthase (e.g. bedaquiline, bedaquiline fumarate or any othercompounds that may have be disclosed in the prior art, e.g. compoundsdisclosed in WO2004/011436), inhibitors of ndh2 (e.g. clofazimine) andinhibitors of cytochrome bd. Additional mycobacterial agents which maybe combined with the compounds of the invention are for examplerifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide;ethambutol; streptomycin; para-aminosalicylic acid; cycloserine;capreomycin; kanamycin; thioacetazone; PA-824; delamanid;quinolones/fluoroquinolones such as for example moxifloxacin,gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides such asfor example clarithromycin, amoxycillin with clavulanic acid;rifamycins; rifabutin; rifapentin; as well as others, which arecurrently being developed (but may not yet be on the market; see e.g.http://www.newtbdrugs.org/pipeline.php).

General Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which may be known to the skilled person ordescribed herein.

EXPERIMENTAL PART

Compounds of formula I may be prepared in accordance with the techniquesemployed in the examples hereinafter (and those methods know by thoseskilled in the art), for example by using the following techniques.

Compounds of formula (I) may be prepared by:

(i) reaction of a compound of formula (II),

wherein the integers are as hereinbefore defined, or a suitablederivative thereof, such as a carboxylic acid ester derivative, with acompound of formula (III)

wherein the integers are as hereinbefore defined, under amide couplingreaction conditions, for example in the presence of a suitable couplingreagent (e.g. 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or hydrochloride thereof)or N,N′-disuccinimidyl carbonate), optionally in the presence of asuitable base (e.g. sodium hydride, sodium bicarbonate, potassiumcarbonate, pyridine, triethylamine, dimethylaminopyridine,diisopropylamine, sodium hydroxide, potassium tert-butoxide and/orlithium diisopropylamide (or variants thereof) and an appropriatesolvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane,chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene,dioxane or triethylamine). Alternatively, the carboxylic acid group ofthe compound of formula (IV) may first be converted under standardconditions to the corresponding acyl chloride (e.g. in the presence ofPOCl₃, PCl₅, SOCl₂ or oxalyl chloride), which acyl chloride is thenreacted with a compound of formula (V), for example under similarconditions to those mentioned above;(ii) coupling of a compound of formula (IV),

wherein the integers are as hereinbefore defined, and LG² represents asuitable leaving group, such as iodo, bromo, chloro or a sulfonate group(for example a type of group that may be deployed for a coupling), witha compound of formula (V),

X¹—H  (V)

wherein the integers are as hereinbefore defined, under standardconditions, for example optionally in the presence of an appropriatemetal catalyst (or a salt or complex thereof) such as Pd(dba)₂,Pd(OAc)₂, Cu, Cu(OAc)₂, CuI, NiCl₂ or the like, with an optionaladditive such as Ph₃P, X-phos or the like, in the presence of anappropriate base (e.g. t-BuONa, or the like) in a suitable solvent (e.g.dioxane or the like) under reaction conditions known to those skilled inthe art.

Other steps that may be mentioned include:

-   -   nucleophilic aromatic substitution reactions    -   other coupling reactions e.g. in which one compound contains a        suitable leaving group such as one described hereinbefore with        respect to LG² (and may particularly represent chloro, bromo or        iodo), with another compound comprising a mutually compatible        “leaving group” or another suitable group such as —B(OH)₂,        —B(OR^(wx))₂ or —SN(R^(wx))₃, in which each R^(wx) independently        represents a C₁₋₆ alkyl group, or, in the case of —B(OR^(wx))₂,        the respective R^(wx) groups may be linked together to form a 4-        to 6-membered cyclic group, thereby forming e.g. a pinacolato        boronate ester group (or may represent iodo, bromo or chloro,        provided that the “leaving groups” are mutually compatible), and        wherein the reaction may be performed in the presence of a        suitable catalyst system, e.g. a metal (or a salt or complex        thereof) such as Pd, CuI, Pd/C, PdCl₂, Pd(OAc)₂, Pd(Ph₃P)₂Cl₂,        Pd(Ph₃P)₄, Pd₂(dba)₃ and/or NiCl₂ (or the like) and a ligand        such as PdCl₂(dppf).DCM, t-Bu₃P, (C₆H₁₁)₃P, Ph₃P or the like, in        a suitable solvent and under reaction conditions known to those        skilled in the art.

It is evident that in the foregoing and in the following reactions, thereaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art, such as extraction, crystallization and chromatography. Itis further evident that reaction products that exist in more than oneenantiomeric form, may be isolated from their mixture by knowntechniques, in particular preparative chromatography, such aspreparative HPLC, chiral chromatography. Individual diastereoisomers orindividual enantiomers can also be obtained by Supercritical FluidChromatography (SCF).

The starting materials and the intermediates are compounds that areeither commercially available or may be prepared according toconventional reaction procedures generally known in the art.

Synthesis of Compound 1 and Compound 2 Synthesis of Intermediate T

Preparation of Intermediate R

Triphenylphosphine (1.89 g, 7.20 mmol), imidazole (735 mg, 10.8 mmol)and iodine (1.37 g, 5.40 mmol) were added to a solution of tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 768mg, 3.60 mmol) in toluene (50 mL). The resulting mixture was refluxedfor 1 hour. The mixture was cooled to 25° C., washed with water (100 mL)and brine (50 mL). The separated organic layer was dried, filtered andthe filtrate was concentrated under vacuum. The residue was purified byflash column chromatography over silica gel (eluent: petroleumether/ethyl acetate 1/0 to 1/1) to give intermediate R (1.20 g, yield:93%).

Preparation of Intermediate S

A mixture of 4-(Trifluoromethoxy)phenylboronic acid (CAS [139301-27-2],510 mg, 2.48 mmol), trans-2-amino-cyclohexanol (23.0 mg, 0.200 mmol) andnickel iodine (62.5 mg, 0.200 mmol) in isopropanol (4 mL) was stirred at25° C. for 30 minutes under nitrogen flow. NaHMDS (2.47 ml, 1 M in THF,2.47 mmol) was added, and the mixture was stirred for 10 minutes undernitrogen flow. Intermediate R (400 mg, 1.24 mmol) in isopropanol (1 mL)was added and the mixture was stirred at 60° C. under microwave for 1hour, at 90° C. for 1 hour and at 120° C. for 5 hours. The mixture wasdiluted with dichloromethane (50 mL), washed with water (2×50 mL) andbrine (20 mL). The organic layer was dried over sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/ethyl acetate5/1) to give intermediate S (230 mg, yield: 52%).

Preparation of Intermediate T

Intermediate S (220 mg, 0.616 mmol) was added to formic acid (5 mL) at0° C. under nitrogen atmosphere. The mixture was stirred at 25° C. for 5hours. The mixture was concentrated under vacuum. The residue wasdissolved into dichloromethane (20 mL). The solution was washed withsaturated aqueous sodium carbonate solution (20 mL), brine (20 mL),dried over sodium sulfate, filtered and concentrated under vacuum togive Intermediate T (150 mg, yield: 85%).

Synthesis of Compound 1 and Compound 2

Preparation of intermediate AY

A mixture of 2-chloro-6-quinolinecarbonitrile (CAS [78060-54-5], 14.7mg, 0.078 mmol), Intermediate T (20.0 mg, 0.078 mmol) and potassiumcarbonate (21.6 mg, 0.156 mmol) in acetonitrile (5 mL) was refluxed for16 hours. The solvent was evaporated under vacuum. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/ethyl acetate 1/1) to give intermediate AY (20.0 mg, yield:62.8%).

Preparation of Intermediate AZ

A solution of intermediate AY (20.0 mg, 0.049 mmol) in NH₃.MeOH (20 mL,7 M NH₃ in MeOH) was hydrogenated at 15° C. (15 psi) with Raney nickel(3 mg) as a catalyst for 16 hours. The catalyst was filtered off and thefiltrate was concentrated under vacuum to give intermediate AZ (20.0 mg,yield: 91.84%).

Preparation of Compound 2

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid(CAS [1216142-18-5], 9.79 mg, 0.044 mmol), HATU (21.7 mg, 0.057 mmol),DIEA (14.8 mg, 0.114 mmol) in CH₂Cl₂ (10 mL) was stirred for 30 minutesat 25° C. Intermediate AZ (20 mg, 0.048 mmol) was added to the mixtureand the mixture was stirred for 2 hours at 25° C. The mixture wasconcentrated under vacuum. The crude product was purified by highperformance liquid chromatography over Gemini (eluent: 0.05% ammonia inwater/methanol 35/65 to 5/95). The desired fractions were collected andconcentrated to give Compound 2 (4.30 mg, 15.91%).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.56 (s, 1H) 7.84 (d, J=8.80 Hz,1H) 7.74 (d, J=8.56 Hz, 1H) 7.59 (s, 1H) 7.55 (d, J=9.29 Hz, 2H) 7.31(d, J=9.78 Hz, 1H) 7.22 (d, J=8.40 Hz, 2H) 7.16 (d, J=8.40 Hz, 2H) 6.59(d, J=9.05 Hz, 1H) 6.13 (br. s., 1H) 4.79 (d, J=5.62 Hz, 2H) 4.33 (s,2H) 4.11 (s, 2H) 3.50 (t, J=8.68 Hz, 1H) 2.97 (q, J=7.42 Hz, 2H)2.65-2.76 (m, 2H) 2.33-2.44 (m, 2H) 1.38 (t, J=7.58 Hz, 3H)

Preparation of Intermediate L

Preparation of Intermediate J

NBS (45.1 g, 254 mmol) and NH₄OAc (5.33 g, 69.2 mmol) were added to asolution of methyl-3-oxovalerate (CAS[30414-53-0], 30 g, 231 mmol) inmethyl t-butylether (600 mL). The mixture was stirred at roomtemperature for 48 h. The mixture was filtered and washed with H₂O,dried over Na₂SO₄ and filtered. The filtrate was concentrated undervacuum. The residue was purified by column chromatography over silicagel (eluent: petroleum ether/ethyl acetate 20/1) to give intermediate J(20.0 g, yield: 35%).

Preparation of Intermediate K

A solution of 5-Chloro-2-pyridinamine (CAS [5428-89-7], 12.0 g, 93.0mmol) and intermediate J (25.0 g, 112 mmol) in ethanol (60 mL) wasrefluxed overnight. The mixture was concentrated under vacuum. Theresidue was dissolved into ethyl acetate (100 mL). The solution waswashed with water (2×100 mL), brine (100 mL), dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography over silica gel (eluent: petroleum ether/ethylacetate 3/1) to give intermediate K (700 mg, yield: 3%).

Preparation of Intermediate L

A mixture of intermediate K (700 mg, 2.10 mmol) and sodium hydroxide(252 mg, 6.30 mmol) in ethanol (2 ml) and H₂O (2 mL) was stirredovernight at room temperature. Water (20 mL) was added and the solutionwas acidified with 2 M aqueous hydrochloride to pH˜3. The solution waslyophilized to give crude intermediate L (2 g).

Preparation of Compound 1

Accordingly, Compound 1 was prepared in the same way as Compound 2starting from intermediate L and intermediate AZ, yielding 0.037 g, 25%.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.83 (d, J=2.51 Hz, 1H) 8.55 (d,J=2.51 Hz, 1H) 7.83 (d, J=8.78 Hz, 1H) 7.75 (d, J=8.53 Hz, 1H) 7.55 (d,J=9.20 Hz, 1H) 7.53 (d, J=6.80 Hz, 1H) 7.22 (d, J=8.80 Hz, 2H) 7.15 (d,J=8.40 Hz, 2H) 6.58 (d, J=8.78 Hz, 1H) 6.26 (t, J=5.27 Hz, 1H) 4.77 (d,J=5.60 Hz, 2H) 4.33 (s, 2H) 4.11 (s, 2H) 3.50 (quin, J=8.85 Hz, 1H) 3.01(q, J=7.53 Hz, 2H) 2.65-2.74 (m, 2H) 2.33-2.43 (m, 2H) 1.41 (t, J=7.53Hz, 3H)

Further Examples Synthesis of Compound 3

Preparation of intermediate A″

A mixture of 4-(4-(trifluoromethoxy)phenyl)piperidine (CAS[180160-91-2], 0.2 g, 0.710 mmol) and 2-chloroquinoline-6-carbonitrile(CAS [78060-54-5], 0.161 g, 0.852 mmol) in pyridine (5 mL) was stirredat 150° C. for 30 minutes under microwave. The mixture was evaporated todryness and diluted with water, extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The residue was purified by silica gel chromatography eluted withpetroleum ether:ethyl acetate=8:1 to afford intermediate A″, 0.13 g,46%.

Preparation of Intermediate B″

To a solution of intermediate A″ (0.13 g, 0.327 mmol) in MeOH (20 mL)was added Raney Nickel (65 mg) and ammonia 4M in MeOH (1 mL) under N₂.The suspension was degassed under vacuum and purged with H2 severaltimes. The mixture was stirred under H2 (50 psi) at 25° C. for 10 hours.The suspension was filtered through a pad of Celite® was washed withMeOH (20 mL). The combined filtrates were concentrated to dryness togive intermediate B″, 0.12 g, 92%.

Preparation of Compound 3

To a solution of intermediate B″ (0.1 g, 0.2497 mmol) in DMF (10 mL)were added 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS[1216142-18-5], 0.067 g, 0.299 mmol), EDCI (0.072 g, 0.3747 mmol), HOBt(0.04 gg, 0.299 mmol) and triethylamine (0.05 g, 0.498 mmol). Themixture was stirred at 80° C. overnight. The reaction mixture was pouredinto water and extracted with ethyl acetate. The combined organic layerswere dried over sodium sulfate and concentrated to dryness. The residuewas purified by silica gel chromatography eluted withdichloromethane:ethyl acetate=10:1 to give Compound 3, 0.055 g, 36%.

¹H NMR (400 MHz, CHLOROFORM-d) δ=9.54 (s, 1H), 7.91 (d, J=9.3 Hz, 1H),7.63-7.50 (m, 3H), 7.35-7.19 (m, 4H), 7.18-7.12 (m, 2H), 7.07 (d, J=9.0Hz, 1H), 6.22 (br. s., 1H), 4.85-4.63 (m, 4H), 3.17-3.07 (m, 2H), 2.98(q, J=7.4 Hz, 2H), 2.89-2.79 (m, 1H), 2.01 (d, J=12.5 Hz, 2H), 1.79 (dq,J=3.8, 12.6 Hz, 2H), 1.39 (t, J=7.5 Hz, 3H).

Synthesis of Compound 4

Preparation of Intermediate C″

Accordingly, intermediate C″ was prepared in the same way asintermediate A″ starting from 2-chloroquinoline-6-carbonitrile CAS[78060-54-5] and 5-fluorooctahydro-cyclopenta[c]pyrrole CAS[1554431-13-8] to give 0.15 g, 91%.

Preparation of Intermediate D″

Accordingly, intermediate D″ was prepared in the same way asintermediate B″ starting from intermediate C″ to give 0.15 g, 99%.

Preparation of Compound 4

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid(CAS [1216142-18-5], 0.07 g, 0.312 mmol), HATU (0.154 g, 0.405 mmol) anddiisopropylethylamine (0.161 g, 1.25 mmol) in DMF (3 mL) was stirred atroom temperature for 1 h. Intermediate D″ (0.089 g, 0.312 mmol) wasadded and the solution was stirred at room temperature overnight. Thesolvent was evaporated under vacuum. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/methanol 10/1). Thedesired fractions were concentrated under vacuum to give Compound 4,0.136 g, 87%.

¹HNMR (400 MHz, CHLOROFORM-d) δ=9.50-9.60 (m, 1H) 7.80-7.87 (m, 1H)7.68-7.76 (m, 1H) 7.49-7.60 (m, 3H) 7.27-7.33 (m, 1H) 6.71-6.78 (m, 1H)6.08-6.17 (m, 1H) 5.18-5.35 (m, 1H) 4.74-4.82 (m, 2H) 3.74-3.85 (m, 2H)3.48-3.57 (m, 2H) 3.02-3.13 (m, 2H) 2.91-3.00 (m, 2H) 2.25-2.40 (m, 2H)1.80-1.88 (m, 1H) 1.70-1.78 (m, 1H) 1.33-1.43 (m, 3H)

Synthesis of Compound 5

Preparation of Intermediate E″

A mixture of 2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.015g, 0.078 mmol), intermediate T (0.02 g, 0.078 mmol) and potassiumcarbonate (0.022 g, 0.156 mmol) in acetonitrile (5 mL) was refluxed for16 hours. The solvent was evaporated under vacuum. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/ethyl acetate 1/1) to give intermediate E″, 0.02 g, 63%.

Preparation of Intermediate F″

Accordingly, intermediate F″ was prepared in the same way asintermediate B″ starting from intermediate E″ to give 0.02 g, 92%.

Preparation of Compound 5

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid(CAS [1216142-18-5], 0.01 g, 0.044 mmol), HATU (0.022 g, 0.057 mmol),diisopropylethylamine (0.015 g, 0.114 mmol) in CH₂Cl₂ (10 mL) wasstirred for 30 minutes at 25° C. Intermediate F″ (0.02 g, 0.048 mmol)was added to the mixture and the mixture was stirred for 2 hours at 25°C. The mixture was concentrated under vacuum. The crude product waspurified by high performance liquid chromatography over Gemini (eluent:0.05% ammonia/methanol 35/65 to 5/95). The desired fractions werecollected and concentrated to give Compound 5, 0.0043 g, 16%.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.56 (s, 1H) 7.84 (d, J=8.80 Hz,1H) 7.74 (d, J=8.56 Hz, 1H) 7.59 (s, 1H) 7.55 (d, J=9.29 Hz, 2H) 7.31(d, J=9.78 Hz, 1H) 7.22 (d, J=8.40 Hz, 2H) 7.16 (d, J=8.40 Hz, 2H) 6.59(d, J=9.05 Hz, 1H) 6.13 (br. s., 1H) 4.79 (d, J=5.62 Hz, 2H) 4.33 (s,2H) 4.11 (s, 2H) 3.50 (t, J=8.68 Hz, 1H) 2.97 (q, J=7.42 Hz, 2H)2.65-2.76 (m, 2H) 2.33-2.44 (m, 2H) 1.38 (t, J=7.58 Hz, 3H)

Synthesis of Compound 6

A solution of intermediate L (0.05 g, 0.222 mmol), HATU (110 mg, 0.289mmol), diisopropylethylamine (0.075 g, 0.577 mmol) in CH₂Cl₂ (10 mL) wasstirred for 30 minutes at 25° C. Intermediate F″ (101 mg, 0.244 mmol)was added to the mixture and the mixture was stirred for 2 hours at 25°C. The mixture was concentrated under vacuum. The crude product waspurified by high performance liquid chromatography over Gemini (eluent:0.05% ammonia/methanol 20/80 to 5/95). The desired fractions werecollected and concentrated to give Compound 6, 0.037 g, 25%.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.83 (d, J=2.51 Hz, 1H) 8.55 (d,J=2.51 Hz, 1H) 7.83 (d, J=8.78 Hz, 1H) 7.75 (d, J=8.53 Hz, 1H) 7.55 (d,J=9.20 Hz, 1H) 7.53 (d, J=6.80 Hz, 1H) 7.22 (d, J=8.80 Hz, 2H) 7.15 (d,J=8.40 Hz, 2H) 6.58 (d, J=8.78 Hz, 1H) 6.26 (t, J=5.27 Hz, 1H) 4.77 (d,J=5.60 Hz, 2H) 4.33 (s, 2H) 4.11 (s, 2H) 3.50 (quin, J=8.85 Hz, 1H) 3.01(q, J=7.53 Hz, 2H) 2.65-2.74 (m, 2H) 2.33-2.43 (m, 2H) 1.41 (t, J=7.53Hz, 3H)

Synthesis of Compound 7

To a solution of intermediate B″ (0.1 g, 0.2497 mmol) in CH₂Cl₂ (15 mL)were added 6-methylimidazo[2,1-B][1,3]thiazole-5-carboxylic acid (CAS[77628-51-4], 0.059 g, 0.324 mmol), HATU (0.142 g, 0.374 mmol) anddiisopropylethylamine (0.064 g, 0.498 mmol). The mixture was stirred atroom temperature overnight. The reaction mixture was poured into waterand extracted with dichloromethane. The combined organic layers weredried over sodium sulfate and concentrated to dryness. The residue waspurified by high performance liquid chromatography (Phenomenex Gemini150×25 mm×10 um, 25 ml/min, mobile phase water (containing 0.1%NH₃.H₂O)/Acetonitrile, gradient from 45/55 to 25/85). The desiredfraction was collected and evaporated to remove off CH₃CN in vacuum. Theresidue was lyophilized to give Compound 7, 0.052 g, 37%.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.31 (d, J=4.5 Hz, 1H), 7.88 (d, J=9.3Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.59-7.51 (m, 2H), 7.27-7.23 (m, 2H),7.19-7.13 (m, 2H), 7.06 (d, J=9.3 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.03(br. s., 1H), 4.80-4.69 (m, 4H), 3.06 (dt, J=2.3, 12.9 Hz, 2H), 2.84(tt, J=3.6, 12.2 Hz, 1H), 2.59 (s, 3H), 2.03-1.95 (m, 2H), 1.78 (dq,J=4.3, 12.7 Hz, 2H).

Synthesis of Compound 8

Preparation of Intermediate BL A mixture of 2-aminopyrazine (CAS[5049-61-6], 12 g, 126.18 mmol) and intermediate J (39.6 g, 189.27 mmol)in EtOH (10 mL) was stirred at 100° C. for 12 h. The solvent was removedin vacuum. The crude product was purified by column chromatography(petroleum ether/ethyl acetate=5/1˜1/1). The product fractions werecollected and the solvent was evaporated to give intermediate BL, 2 g,8%.

Preparation of Intermediate BM

To a solution of intermediate BL (5 g, 24.36 mmol) in MeOH (20 mL) wasadded platine dioxide (500 mg) under N₂, followed by addition a drop ofcon HCl. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H₂ (15 psi) at 25° C. for10 hours. The suspension was filtered through a pad of Celite® and thepad was washed with methanol (50 mL). The combined filtrates wereconcentrated to dryness to give intermediate BM, 5 g, 98%.

Preparation of Intermediate BN

To a solution of intermediate BM (5 g, 23.89 mmol) in MeOH (75 mL) wasadded formaldehyde aqueous solution (9.7 g, 119.47 mmol, 37%) at 0° C.,followed by addition sodium borocyanohydride (7.5 g, 119.47 mmol) and adrop of acetic acid (0.2 mL). Then the mixture was stirred at roomtemperature for overnight. 10% NH₄Cl solution (25 mL) was addeddropwise. The mixture was extracted with ethyl acetate, the combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andthe solvent was evaporated under vacuum. The residue was purified bycolumn chromatography over silica gel (dichloromethane/methanol=15:1 to10:1) to give intermediate BN, 1.3 g, 24%.

Preparation of Intermediate BO

To a solution of intermediate BN (0.55 g, 2.46 mmol) in MeOH (25 mL) andwater (5 mL) was added lithium hydroxide monohydrate (0.52 g, 12.32mmol). The mixture was stirred at room temperature for 10 h. The solventwas removed in vacuum to dryness. The residue was purified by highperformance liquid chromatography (DuraShell 150×25 mm×5 μm, 25 ml/min,water (containing 0.05% HCl)/Acetonitrile from 100/0 to 70/30). Thedesired fraction was collected and evaporated to remove off acetonitrilein vacuum. The residue was lyophilized to give intermediate BO, 0.4 g,78%.

Preparation of Compound 8

A solution of intermediate BO (0.03 g, 0.143 mmol), HATU (0.071 g, 0.186mmol) and diisopropylethylamine (0.056 g, 0.430 mmol) in DMF (3 mL) wasstirred at room temperature for 1 h. Intermediate B″ (0.058 g, 0.143mmol) was added and the solution was stirred at room temperatureovernight. The solvent was evaporated under vacuum. The residue waspurified by high performance liquid chromatography over Waters XbridgePrep OBD C18 100×19 mm×5 μm (eluent: water (0.05% ammonia hydroxidev/v)-MeOH 25/75 to 5/95). The desired fractions were lyophilized undervacuum to give Compound 8, 0.045 g, 53%.

¹H NMR (400 MHz, CHLOROFORM-d) ppm 7.84-7.89 (m, 1H) 7.68-7.73 (m, 1H)7.47-7.56 (m, 2H) 7.21-7.25 (m, 2H) 7.12-7.18 (m, 2H) 7.02-7.07 (m, 1H)5.97-6.02 (m, 1H) 4.69 (m, 4H) 4.34 (m, 2H) 3.65 (s, 2H) 3.00-3.09 (m,2H) 2.78-2.82 (m, 2H) 2.67-2.75 (m, 2H) 2.45-2.50 (s, 3H) 1.94-2.02 (m,2H) 1.71-1.83 (m, 3H) 1.23 (m, 3H)

Synthesis of Compound 9

Preparation of Intermediate G″

Accordingly, intermediate G″ was prepared in the same way asintermediate A″ starting from 2-chloroquinoline-6-carbonitrile (CAS[78060-54-5] and 1-(4-Trifluoromethoxy-phenyl)-piperazine CAS[187669-62-1] affording 0.15 g, 84%.

Preparation of Intermediate H″

Accordingly, intermediate H″ was prepared in the same way asintermediate B″ starting from intermediate G″ affording 0.15 g, 96%.

Preparation of Compound 9

A solution of 6-methylimidazo[2,1-B][1,3]thiazole-5-carboxylic acid (CAS[77628-51-4], 0.018 g, 0.1 mmol), HATU (0.049 g, 0.13 mmol) anddiisopropylethylamine (0.026 g, 0.20 mmol) in CH₂Cl₂ (5 mL) was stirredat room temperature for 1 h. Intermediate H″ (0.04 g, 0.1 mmol) wasadded and the solution was stirred at room temperature for 2 hours. Thesolution was washed with water (10 mL), brine (5 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was washed withmethanol (3 mL). The precipitate was concentrated under vacuum to affordCompound 9, 0.032 g, 57%

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.26-8.37 (m, 1H) 7.86-7.96 (m, 1H)7.70-7.78 (m, 1H) 7.50-7.63 (m, 2H) 7.11-7.20 (m, 2H) 7.01-7.07 (m, 1H)6.92-7.00 (m, 2H) 6.85-6.91 (m, 1H) 5.97-6.07 (m, 1H) 4.71-4.82 (m, 2H)3.83-3.99 (m, 4H) 3.25-3.40 (m, 4H) 2.54-2.66 (m, 3H)

Synthesis of Compound 10

A solution of intermediate H″ (0.1 g, 0.249 mmol),2-ethyl-5H,6H,7H,8H-imidazo-[1,2-a]pyridine-3-carboxylic acid CAS[1529528-99-1], 0.107 g, 0.249 mmol), HATU (123 mg, 0.323 mmol) anddiisoprpopylethylamine (96 mg, 0.746 mmol) in CH₂Cl₂ (3 mL) was stirredat room temperature for 1 h. The solvent was evaporated under vacuum.The residue was purified by high performance liquid chromatography overPhenomenex Gemini C18 250×21.2 mm×5 μm (eluent: water (0.05% ammoniahydroxide v/v)-MeOH 25/75 to 0/100). The desired fractions werelyophilized under vacuum to give Compound 10, 0.074 g, 52%. ¹HNMR (400MHz, CHLOROFORM-d) ppm 7.87-7.93 (m, 1H) 7.69-7.75 (m, 1H) 7.50-7.59 (m,2H) 7.10-7.18 (m, 2H) 7.01-7.07 (m, 1H) 6.92-6.98 (m, 2H) 5.95-6.03 (m,1H) 4.66-4.74 (m, 2H) 4.25 (m, 2H) 3.86-3.96 (m, 4H) 3.28-3.37 (m, 4H)2.83-2.91 (m, 2H) 2.65-2.75 (m, 2H) 1.85-2.00 (m, 4H) 1.20-1.28 (m, 3H)

Synthesis of Compound 11

Preparation of Intermediate I″

To a solution of 4-(Trifluoromethoxy)phenethylamine (CAS [170015-99-3],0.5 g, 2.44 mmol) in DMF (30 mL) was added2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.460 g, 2.44 mmol)and potassium carbonate (0.674, 4.87 mmol). The mixture was stirred at100° C. for 10 h. The mixture was diluted with water (30 mL) andextracted with ethyl acetate (30 mL×3). The organic layers were driedover sodium sulfate and concentrated in vacuum. The crude product waspurified by column chromatography (petroleum ether/ethyl acetate=5/1).The product fractions were collected and the solvent was evaporated togive intermediate I″, 0.2 g, 23%.

Preparation of Intermediate J″

Sodium hydride (0.027 g, 0.67 mmol, 60% in mineral oil) was added to amixture of intermediate I″ (0.16 g, 0.45 mmol) in DMF (10 mL) at 0° C.under N₂ atmosphere. The mixture was stirred at 0° C. for 30 minutes.Methyliodide (0.04 mL, 0.537 mmol) was added to the mixture and stirredat 25° C. for 10 hours. The mixture was quenched with aq. NH₄Cl, dilutedwith water. The mixture was extracted with ethyl acetate (3×10 mL). Theorganic layer was washed with brine, dried over sodium sulfate, filteredand concentrated. The residue was purified by column chromatography oversilica gel (petroleum ether/ethyl acetate=10/1˜4/1). The productfractions were collected and the solvent was evaporated to giveintermediate J″, 0.18 g, 84%.

Preparation of Intermediate K″

To a solution of intermediate J″ (0.18 g, 0.485 mmol) in ammonia 4M inmethanol (10 mL) was added Raney Nickel (50 mg) under N₂. The suspensionwas degassed under vacuum and purged with H2 several times. The mixturewas stirred under H2 (15 psi) at 25° C. for 10 hours. The suspension wasfiltered through a pad of Celite® and the pad was washed with methanol(10 mL). The combined filtrates were concentrated in vacuum to giveintermediate K″, 0.18 g, 99%.

Preparation of Compound 11

To a solution of 6-Methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid(CAS [77628-51-4], 0.096 g, 0.53 mmol) in DMF (10 mL) was addedintermediate K″ (0.18 g, 0.48 mmol), HATU (237.02 mg, 0.62 mmol) anddiisopropylethylamine (0.186 g, 1.44 mmol). The mixture was stirred atroom temperature overnight. The mixture was diluted with water (20 mL)and extracted with dichloromethane (10 mL×3). The organic layers weredried over sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by high performance liquid chromatography (WatersXbridge Prep OBD C18 150×30×5μ, 25 ml/min, mobile phase: water(containing 0.05% NH₃.H₂O)/acetonitrile, gradient from 52/58 to 22/78).The desired fraction was collected and evaporated to remove offacetonitrile in vacuum. The residue was lyophilized to give Compound 11,0.091 g, 34%.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.32 (d, J=4.4 Hz, 1H), 7.83 (d, J=9.3Hz, 1H), 7.75-7.68 (m, 1H), 7.59-7.50 (m, 2H), 7.31-7.27 (m, 2H), 7.14(d, J=7.9 Hz, 2H), 6.89 (d, J=4.4 Hz, 1H), 6.82 (d, J=9.3 Hz, 1H), 6.01(br. s., 1H), 4.77 (d, J=5.7 Hz, 2H), 3.90 (t, J=7.5 Hz, 2H), 3.13 (s,3H), 2.98 (t, J=7.3 Hz, 2H), 2.59 (s, 3H).

Synthesis of Compound 12

Preparation of Intermediate CD

A mixture of 5-chloro-3-iodopyridin-2-amine (CAS [211308-81-5], 4 g,15.72 mmol), 2,4-Hexadione (CAS [3002-24-2], 4.50 g, 34.58 mmol), cesiumcarbonate (5.12 g, 15.71 mmol), BINOL (900.20 mg, 3.14 mmol) and copperiodide (299.39 mg, 1.57 mmol) in DMSO (50 mL) was stirred for 15 hoursunder N₂ flow. Brine and ethyl acetate were added to the mixture. Theorganic layer was separated, washed with brine, dried over MgSO₄ andfiltered. The filtrate was concentrated. The crude product was purifiedby column chromatography over silica gel (eluent: ethyl acetate/hexanefrom 0 to 1/1). The desired fractions were collected and concentrated togive intermediate CD, 2.5 g, 67%

Preparation of Intermediate CE

Sodium hydride (0.354 g, 8.85 mmol) was added to a solution ofintermediate CD (2.2 g, 7.38 mmol) in THF (40 mL) at 0° C. After stirredfor 30 minutes, methyl iodide (1.26 g, 8.85 mmol) was added. The mixturewas warmed up to 25° C. and stirred for 3 hours. The mixture was pouredinto ice water. The mixture was extracted with ethyl acetate (50 mL×2).The organic layers were combined, washed with brine, dried over MgSO₄and filtered. The filtrate was concentrated. The crude product waspurified by column chromatography over silica gel (eluent: ethylacetate/petroleum ether from 0 to 1/3). The filtrate was concentrated togive intermediate CE, 1.6 g, 86%.

Preparation of Intermediate AV

Intermediate AV was prepared in the same way as intermediate S, startingfrom intermediate R and Phenylboronic acid CAS [98-80-6], yielding 0.3g, 62%.

Preparation of Intermediate AW

Accordingly, intermediate AW was prepared in the same way asintermediate T, starting from intermediate AV, yielding 0.27 g, 99%.

Preparation of Intermediate N″

Sodium hydroxide (0.225 g; 5.62 mmol) was added to a solution ofintermediate CE (0.5 g; 1.88 mmol) in EtOH (7.5 mL) and H₂O (7.5 mL) andthe mixture was stirred at 70° C. for 48 h. The mixture was evaporatedin vacuo to give a colorless oil which was azeotroped with toluene(twice) to give 0.777 g of intermediate N″ as white solid (quant).

Preparation of Intermediate L″

A suspension of intermediate AW (0.169 g, 806 μmol),2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.304 g, 1.61 mmol)and potassium carbonate (0.557 g, 4.03 mmol) in DMSO (3 mL) was heatedto 120° C. using a single mode microwave (Biotage Initiator 60) with apower output ranging from 0 to 400 W for 30 min [fixed hold time on].The reaction was quenched with water and extracted with EtOAc (3×). Thecombined organic phases were washed with water (twice) and brine (3×),dried over MgSO₄, filtered and evaporated to dryness. The crude waspurified by preparative LC (irregular silica 15-40 m, 12 g GraceResolv,dry loading (silica), mobile phase: heptane/EtOAc 90/10 to 70/30) toobtain 0.142 g of intermediate L″ (54%).

Preparation of Intermediate M″

A mixture of intermediate L″ (0.099 g, 0.304 mmol) and Ra—Ni (77.5 mg,1.32 mmol) in ammonia 7M in MeOH (3.3 mL) was hydrogenated at roomtemperature under 2 bar overnight. The mixture was filtered through apad of Celite® and rised with EtOAc. The filtrate was evaporated untildryness to give 0.098 g of intermediate M″ as a pale grey solid (98%).

Preparation of Compound 12

Diisopropylethylamine (0.12 mL, 0.706 mmol) and HATU (0.14 g, 0.367mmol) were successively added to a solution of intermediate N″ (0.074 g,0.282 mmol) in DMF (7.8 mL). The resulting mixture was stirred at roomtemperature for 30 min, before the addition of intermediate M″ (0.093 g,0.282 mmol) and the mixture was stirred at room temperature overnight.The reaction mixture was diluted with EtOAc and washed with an aq. sat.NaHCO₃ solution (twice) and brine (twice). The organic phase was driedover MgSO₄, filtered and evaporated to dryness. The crude was purifiedby preparative LC (Irregular silica 15-40 m, 14 g Grace Resolv, dryloading (silica), mobile phase gradient: from Heptane/EtOAc 90/10 to50/50) to obtain a solid which was triturated in Et₂O, filtered anddried under vacuum to obtain 0.079 g of Compound 12 as white solid(51%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (t, J=5.8 Hz, 1H) 8.27 (d, J=2.0Hz, 1H) 8.21 (d, J=2.0 Hz, 1H) 7.99 (d, J=9.1 Hz, 1H) 7.62 (s, 1H) 7.55(s, 2H) 7.17-7.34 (m, 5H) 6.70 (d, J=9.1 Hz, 1H) 4.59 (d, J=6.1 Hz, 2H)4.23 (s, 2H) 4.01 (s, 2H) 3.80 (s, 3H) 3.34-3.50 (m, 1H) 3.16 (q, J=7.6Hz, 2H) 2.55-2.68 (m, 2H) 2.27-2.44 (m, 2H) 1.21 (t, J=7.6 Hz, 3H).

Synthesis of Compound 13

Preparation of intermediate O″

A suspension of intermediate AW (0.127 g, 750 μmol),2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.283 g, 1.50 mmol),and Potassium tert-butoxide (0.421 g, 3.75 mmol) in DMSO (2.8 mL) washeated to 120° C. using a single mode microwave (Biotage Initiator 60)with a power output ranging from 0 to 400 W for 30 min [fixed hold timeon]. The reaction was quenched with water and extracted with EtOAc (3×).The combined organic phases were washed with water (2×) and brine (3×),dried over MgSO₄, filtered and evaporated to dryness. The crude productwas purified by preparative LC (irregular silica 15-40 m, 24 gGraceResolv, dry loading (silica), mobile phase: heptane/EtOAc 90/10 to50/50) to obtain 0.143 g of intermediate O″ as yellow solid (67%).

Preparation of Intermediate P″

A mixture of intermediate O″ (0.141 g, 0.494 mmol) and Raney Nickel(0.126 g, 2.15 mmol) in ammonia 7M in MeOH (5.4 mL) was hydrogenated atroom temperature under 2 bar overnight. The reaction mixture wasfiltered over Celite®, rinsed with EtOAc and evaporated to dryness toobtain 0.138 g of intermediate P″ as white solid (97%).

Preparation of Compound 13

To a solution of intermediate N″ (0.17 g, 0.653 mmol) and intermediateP″ (0.156 g, 0.539 mmol) in DMF (18 mL) were added HATU (0.323 g, 0.849mmol) and diisopropylethylamine (0.28 mL, 1.63 mmol) and the mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith EtOAc and washed with an aq. sat. NaHCO₃ solution (twice) and brine(twice). The combined organic phases were dried over MgSO₄, filtered andevaporated to dryness. The crude was purified by preparative LC(Irregular silica 15-40 μm, 24 g Grace Resolv, dry loading (silica),mobile phase gradient: from Heptane/EtOAc 90/10 to 10/90) to obtain0.167 g as a white solid which was triturated in Et₂O and EtOH, filteredand dried under vacuum to obtain 0.116 g of Compound 13 as a white solid(35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.35 (t, J=5.9 Hz, 1H) 8.27 (s, 1H) 8.21(s, 1H) 8.03 (d, J=8.9 Hz, 1H) 7.65 (s, 1H) 7.58 (s, 2H) 7.34-7.45 (m,4H) 7.24-7.29 (m, 1H) 6.78 (d, J=8.6 Hz, 1H) 4.60 (d, J=5.6 Hz, 2H) 4.51(t, J=8.1 Hz, 2H) 3.97-4.10 (m, 3H) 3.81 (s, 3H) 3.13-3.19 (m, 2H) 1.21(br t, J=7.6 Hz, 3H).

Synthesis of Compound 14

Preparation of Intermediate CG

A solution of 2-aminopyridine (CAS [504-29-0], 4.0 g; 42.5 mmol) in THF(220 mL) was cooled to 5° C., before the addition of ethylpropionylacetate (CAS [4949-44-4], 6.1 mL; 42.5 mmol), IodobenzeneDiacetate (CAS [3240-34-4], 13.7 g; 42.5 mmol) and BF₃.OEt₂ (556 μL;2.13 mmol). The resulting mixture was allowed to warm to rt, thenstirred at rt overnight. The mixture was poured into saturated aqueousNaHCO₃ and extracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated to give 18.8 gas an orange solid. The crude was taken-up in Et₂O, leading toprecipitation. The precipitate was filtered to give 3.8 g of crude as anoff-white solid (41%). The filtrate was purified by preparative LC(Regular silica 30 μm, 25 g, liquid loading (CH₂Cl₂), mobile phasegradient: from Heptane/EtOAc 100/0 to 50/50) to obtain 1.7 g ofintermediate 30 as an off-white solid which was taken-up in Et₂O, thesolid was filtered and dried under high vacuum to give 1.2 g ofintermediate CG as a white solid (13%).

Preparation of Intermediate CH

A solution of intermediate CG (1.2 g; 5.50 mmol) in MeOH (27 mL) wasdegassed by N₂ bubbling for 10 min before the addition of Platinum Oxide(125 mg; 0.55 mmol) and HCl (125 μL; 1.50 mmol). The resulting mixturewas hydrogenated at rt under 1 bar overnight. EtOAc was added and themixture was filtered through a pad of Celite®, the filtrate wasconcentrated until dryness to give 1.4 g of intermediate CH ascolourless oil (quant).

Preparation of Intermediate CI

Lithium hydroxide monohydrate (170 mg; 4.05 mmol) was added to asolution of intermediate CH (300 mg; 1.35 mmol) in MeOH (3 mL) and H₂O(158 μL). The resulting mixture was stirred at 50° C. for 48 h. Thesolvent was evaporated in vacuo until dryness to give an off-white gumwhich was azeotroped with toluene (twice), then dried under high vacuumto give 0.353 g of intermediate CI as an off-white solid (used as suchin the next step).

Preparation of Compound 14

Diisopropylethylamine (0.516 mL; 3.00 mmol) and HATU (0.593 g; 1.56mmol) were added successively to a solution of intermediate CI (0.24 g;1.20 mmol) in DMF (36 mL).

The resulting mixture was stirred at room temperature for 30 min, beforethe addition of intermediate B″ (0.481 g; 1.20 mmol) and the mixture wasstirred at room temperature for 2 h. The reaction mixture was evaporatedin vacuo until dryness then diluted with EtOAc and washed with brine(twice). The organic layer was dried over MgSO₄, filtered and evaporatedto dryness. The crude was purified by preparative LC (Regular silica 30m, 12 g Interchim, dry loading (Celite®), mobile phase gradient: fromHeptane/EtOAc/MeOH 90/8/2 to 50/40/10) to obtain 0.2 g as white solid.The solid was triturated in Et₂O, filtered and dried under high vacuumto give 0.126 g of Compound 14 as white solid (18%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (t, J=5.8 Hz, 1H) 7.99 (d, J=9.1Hz, 1H) 7.47-7.58 (m, 3H) 7.40 (d, J=7.8 Hz, 2H) 7.28 (d, J=9.1 Hz, 3H)4.70 (br d, J=13.6 Hz, 2H) 4.50 (d, J=6.1 Hz, 2H) 4.00 (t, J=5.6 Hz, 2H)2.86-3.03 (m, 3H) 2.70 (m, 2H) 2.63 (m 2H) 1.76-1.93 (m, 6H) 1.59-1.70(m, 2H) 1.10 (t, J=7.6 Hz, 3H).

Synthesis of Compound 15 & Compound 16

Preparation of Intermediates Q″

To a solution of 3,4-dimaminobenzonitrile (CAS [17626-40-3], 1 g, 7.51mmol) in MeOH (20 ml) was added ethylglyoxalate (6.81 ml, 34.35 mmol,35%). After stirring overnight at room temperature, the precipitate wascollected and washed with methanol (10 ml) to give a mixture ofintermediate Q″, 0.6 g, 47%.

Preparation of Intermediates R″

Intermediate Q″ (0.6 g, 3.5 mmol) was dissolved in phosphoryl chloride(20 mL). The mixture was heated to reflux for about 2 h. The mixture waspoured into water and basified with aqueous NaHCO₃ till pH=8 andextracted with dichloromethane (30 ml×3). The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography eluted with petroleum ether:ethyl acetate=10:1to afford product as a mixture of intermediate R″, 0.6 g, 90%.

Preparation of Intermediate S″

A mixture of intermediates R″ (0.5 g, 2.65 mmol),N-Methyl-N-[4-(trifluoromethoxy) benzyl]amine (0.6 g, 2.91 mmol) andpotassium carbonate (0.73 g, 5.3 mmol) in acetonitrile (30 mL) wasstirred at 100° C. for 10 h. The mixture was evaporated to dryness anddiluted with water (30 mL), extracted with ethyl acetate (50 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography eluted with petroleumether:ethyl acetate=8:1 to afford product as a mixture of intermediatesS″, 0.6 g, 63%.

Preparation of Intermediates T″

To a solution of intermediates S″ (0.5 g, 1.4 mmol) in MeOH (50 mL) wasadded Raney Nickel (0.25 g) and ammonia in MeOH (10 mL, 4M) under N₂.The suspension was degassed under vacuum and purged with H2 severaltimes. The mixture was stirred under H₂ (50 psi) at 25° C. for 10 hours.The suspension was filtered through a pad of Celite® was washed withMeOH (20 mL). The combined filtrates were concentrated to dryness. Theresidue was purified by high performance liquid chromatography(Phenomenex Synergi C18, 250×21.2 mm×4 μm, 25 ml/min, water (containing0.05% HCl)/Acetonitrile gradient from 77/23 to 57/43). The desiredfraction was collected and evaporated to remove off acetonitrile invacuum. The residue was adjusted to pH=9 with aqueous NaHCO₃ solution(20 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuum to giveintermediate T₁″, 0.1 g, 20% and T₂″, 0.3 g, 59%.

Preparation of Compound 15

To a solution of intermediate T₁″ (0.1 g, 0.276 mmol) in CH₂Cl₂ (25 mL)was added 6 chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS[1216142-18-5], 0.056 g, 0.251 mmol), HATU (0.124 g, 0.326 mmol) anddiisopropylethylamine (0.084 g, 0.653 mmol). The mixture was stirred atroom temperature overnight. The reaction mixture was poured into waterand extracted dichloromethane. The combined organic layers were driedover Na₂SO₄ and concentrated to dryness. The residue was purified byhigh performance liquid chromatography (Waters Xbridge Prep OBD C18150×30×5μ, 20 ml/min, water (containing 0.05% NH₃.H₂O)/Methanol gradientfrom 25/75 to 0/100). The desired fraction was collected and evaporatedto remove off methanol in vacuum. The residue was lyophilized affordingCompound 15, 0.054 g, 38%.

1H NMR (400 MHz, CHLOROFORM-d) δ 9.57 (s, 1H), 8.50 (s, 1H), 7.86 (s,1H), 7.75-7.68 (m, 1H), 7.63 (dd, J=1.5, 8.6 Hz, 1H), 7.56 (d, J=9.3 Hz,1H), 7.36-7.29 (m, 3H), 7.18 (d, J=7.9 Hz, 2H), 6.21 (br. s., 1H), 4.97(s, 2H), 4.86 (d, J=5.3 Hz, 2H), 3.28 (s, 3H), 3.01 (q, J=7.8 Hz, 2H),1.42 (t, J=7.5 Hz, 3H).

Preparation of Compound 16

To a solution of intermediate T₂″ (0.15 g, 0.414 mmol) in CH₂Cl₂ (25 mL)was added 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS[1216142-18-5], 0.085 g, 0.376 mmol), HATU (0.186 g, 0.489 mmol) anddiisopropylethylamine (0.126 g, 1.11 mmol). The mixture was stirred atroom temperature overnight. The reaction mixture was poured into waterand extracted dichloromethane. The combined organic layers were driedover Na₂SO₄ and concentrated to dryness. The residue was triturated withmethanol (20 mL) and filtered to afford Compound 16, 0.121 g, 56%.

1H NMR (400 MHz, CHLOROFORM-d) δ 9.56 (d, J=1.3 Hz, 1H), 8.49 (s, 1H),7.90 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.41 (dd,J=1.7, 8.5 Hz, 1H), 7.36-7.28 (m, 3H), 7.18 (d, J=8.2 Hz, 2H), 6.24 (br.s., 1H), 4.96 (s, 2H), 4.86 (d, J=5.7 Hz, 2H), 3.27 (s, 3H), 3.02 (q,J=7.5 Hz, 2H), 1.43 (t, J=7.6 Hz, 3H).

The following compounds were also prepared in accordance with theprocedures described herein:

Synthesis of Compound 27

Intermediate U″

Ethyl-2-butynoate (CAS [4341-76-8], 6.2 mL, 54.0 mmol) was added to asolution of 1-aminopyridinium iodide (CAS [6295-37-0], 10 g, 45 mmol)and potassium carbonate (7.5 g, 54 mmol) in DMF (100 mL). The resultingmixture was stirred at room temperature for 72 h. The mixture wasevaporated to dryness and the residue was solubilized in EtOAc andwashed with brine (3×). The organic layer was dried over MgSO₄, filteredand evaporated to dryness to give 5.1 g of intermediate U″ as a brownsolid (55%).

Intermediate V″

Intermediate V″ was prepared in accordance with the following procedure:aqueous sodium hydroxide 8M (e.g. about 164 mmol) is added to a solutionof intermediate U″ (e.g. about 32.1 mmol) in THF (e.g. about 39 mL) andmethanol (e.g. about 39 mL). The resulting mixture may be stirred ate.g. 70° C. overnight. HCl (1M) may be added to the mixture untilpH-7-8. The resulting precipitate may be filtered and dried under highvacuum to give intermediate V″ as an off-white solid.

A solution of intermediate V″ (0.1 g, 0.57 mmol), HATU (0.237 g, 0.62mmol) and triethylamine (0.237 mL, 1.70 mmol) in DMF (7 mL) was stirredat room temperature for 30 min before the addition of intermediate H″(0.24 g, 0.60 mmol) in DMF (5 mL). The resulting mixture was stirred atroom temperature for 2 h. The mixture was evaporated to dryness. Theresidue was solubilized in EtOAc and washed with an aq. solution ofNaHCO₃ (1%) (2×), water and brine. The organic layer was dried overMgSO₄, filtered and evaporated to dryness. The crude product waspurified by preparative LC (Regular SiOH 30 μm, 25 g Interchim, dryloading (Celite®), mobile phase gradient DCM/MeOH from 100/0 to 95/5) togive 0.152 g of Compound 27 as a white solid (38%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.67 (d, J=6.9 Hz, 1H), 8.18 (t, J=5.8Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.67 (s, 1H),7.59 (s, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.31 (d, J=9.5 Hz, 1H), 7.24 (d,J=8.8 Hz, 2H), 7.09 (d, J=9.1 Hz, 2H), 6.98 (t, J=6.9 Hz, 1H), 4.60 (d,J=6.0 Hz, 2H), 3.86-3.82 (m, 4H), 3.33-3.30 (m, 4H), 2.60 (s, 3H)

Synthesis of Compound 28

Preparation of Intermediate W″

A mixture of 2-chloroquinoline-6-carbonitrile ([78060-54-5], 0.464 g,2.46 mmol), trans-6-(Trifluoromethyl)-3-azabicyclo[3.1.0]-hexanehydrochloride ([1212322-57-0], 0.6 g, 3.20 mmol) and potassium carbonate(1.02 g, 7.38 mmol) in DMF (19 mL) was heated to 120° C. overnight. Themixture was evaporated to dryness. The residue was solubilized in EtOAcand washed with brine (2×), dried over MgSO₄, filtered and evaporated todryness. The crude product was purified by preparative LC (irregularSiOH, 15-40 μm, 80 g, Grace, dry loading (silica), mobile phase gradientHeptane/EtOAc from 90/10 to 70/30) to give 0.3 g of intermediate W″ as awhite solid (40%).

Preparation of Intermediate X″

Accordingly, intermediate X″ was prepared in the same way asintermediate B″, starting from intermediate W″, and yielding 0.291 g, asa white powder, 97%.

Preparation of Compound 28

To a solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylicacid ([1216142-18-5], 0.066 g, 0.288 mmol) in DCM (2.9 mL) andtriethylamine (0.10 mL) were added EDCI (0.083 g, 0.432 mmol) and HOBt(0.059 g, 0.434 mmol) and the mixture was stirred at room temperaturefor 30 min. Intermediate X″ (0.094 g, 0.306 mmol) was added and themixture was stirred at room temperature for 8 h, then heated to 80° C.for 5 h. The mixture was cooled to room temperature and washed withwater (2×). The organic layer was dried over MgSO₄, filtered andevaporated to dryness. The crude product was purified by preparative LC(irregular SiOH, 15-40 m, 24 g, Grace, dry loading (silica), mobilephase gradient Heptane/EtOAc from 90/10 to 10/90) to give 0.022 g ofCompound 28 as white solid (15%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.09 (d, J=1.6 Hz, 1H), 8.54 (t, J=6.0Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.69-7.64 (m, 2H), 7.55 (s, 2H), 7.46(dd, J=9.6, 2.0 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H),3.94 (d, J=10.7 Hz, 2H), 3.54 (br d, J=10.1 Hz, 2H), 3.00 (q, J=7.6 Hz,2H), 2.20 (br s, 2H), 1.86-1.80 (m, 1H), 1.25 (t, J=7.6 Hz, 3H).

Characterising Data Table Meting Point LCMS Compound (Kofler UV MW BPM1/LCMS No or DSC) Rt Area % exact BPM2 Method 1 3.69 95.0 620.2 621.2Method A 2 3.52 100.0 619.2 620.2 Method A

Further Characterising Data

LCMS Compound Meting Point BPM1/ LCMS No (Kofler or DSC) Rt UV Area % MWexact BPM2 Method Cpd 3 3.3 95.0 607.2 608.1 Method D Cpd 17 4.23 97.4567.2 568.1 Method C Cpd 7 3.19 97.4 565.2 566.1 Method D Cpd 18 3.2997.7 567.2 568.1 Method D Cpd 9 3.19 100.0 566.2 567.1 Method D Cpd 19 399.3 525.1 526.1 Method D Cpd 5 or 3.52 100.0 619.2 620.2 Method D Cpd 2Cpd 16 3.8 100.0 568.2 569.1 Method D Cpd 6 or 3.69 95.0 620.2 621.2Method D Cpd 1 Cpd 15 3.86 100.0 568.2 569.1 Method D Cpd 20 3.3 98.2567.2 568.1 Method D Cpd 21 3.82 97.1 620.2 621.3 Method D Cpd 22 3.8998.9 621.2 622.2 Method D Cpd 23 3.74 94.4 548.2 549.2 Method D Cpd 42.64 98.3 491.2 492.2 Method D Cpd 8 3.01 99.8 592.3 593.2 Method D Cpd10 2.94 99.7 578.3 579.2 Method D Cpd 24 2.48 95.1 483.2 484.1 Method DCpd 25 2.51 97.5 477.2 478.1 Method D Cpd 11 5.54 98.4 539.2 540.1Method E Cpd 12 171.59° C./−59.2 Jg−1, 3.68 99.4 549.2 550.3/ Method B25° C. to 608.7 350° C./10° C.min/40 μl [M + CH₃COO]⁻ Al Cpd 14 188.28°C./−72.04 Jg−1, 3.49 97.7 577.3 578.3/ Method B 25° C. to 636.7 350°C./10° C.min/40 μl [M + CH₃COO]⁻ Al Cpd 13 208.76° C./−94.35 Jg−1, 3.42100.0 509.2 510.2/ Method B 25° C. to 508.3 350° C./10° C.min/40 μl AlCpd 26 207.61° C./−95.26 J/g 3.55 98.2 559.6 560.2/ Method B (DSC: 25°C. to 618.5 350° C./10° C.min/40 μl [M + CH₃COO]⁻ Al) Cpd 27 217.14°C./−83.66 J/g 3.4 96 560.2 561.2/ Method B (DSC: 25° C. to 619.5 350°C./10° C.min/40 μl [M + CH₃COO]⁻ Al) Cpd 28 251.69° C./−79.88 J/ 3.398.8 513.2 514.2/ Method B g{circumflex over ( )}−1, 25° C. to 512.3350° C./10° C.min/40 μl Al (DSC: 25° C. to 350° C./10° C.min/40 μl Al)

Analytical Methods LCMS

The mass of some compounds was recorded with LCMS (liquid chromatographymass spectrometry). The methods used are described below.

General Procedure LCMS Methods A

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time, etc) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (R_(t))and ions. If not specified differently in the table of data, thereported molecular ion corresponds to the [M+H]⁺ (protonated molecule)and/or [M−H]⁻ (deprotonated molecule). In case the compound was notdirectly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺,[M+HCOO]⁻, etc). For molecules with multiple isotopic patterns (Br, Cl .. . ), the reported value is the one obtained for the lowest isotopemass. All results were obtained with experimental uncertainties that arecommonly associated with the method used.

Hereinafter, “MSD” Mass Selective Detector, “DAD” Diode Array Detector.

TABLE LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Method Mobile Run code InstrumentColumn phase gradient Flow time 50 MethodA Agilent: Agilent: A: CF₃COOH90% A for 0.8 min, 0.8 10.5 1100/1200- TC-C18 0.1% in water, to 20% A in3.7 min, 50 DAD and (5 μm, B: CF₃COOH held for 3 min, back MSD 2.1 × 50mm) 0.05% in to 90% A in 2 min. CH₃CN

When a compound is a mixture of isomers which give different peaks inthe LCMS method, only the retention time of the main component is givenin the LCMS table.

Further Methods General Procedure

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (R_(t))and ions. If not specified differently in the table of data, thereported molecular ion corresponds to the [M+H]⁺ (protonated molecule)and/or [M−H]⁻ (deprotonated molecule). In case the compound was notdirectly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺,[M+HCOO]⁻, etc. . . . ). For molecules with multiple isotopic patterns(Br, Cl . . . ), the reported value is the one obtained for the lowestisotope mass. All results were obtained with experimental uncertaintiesthat are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “RT” roomtemperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” HighStrength Silica, “DAD” Diode Array Detector.

TABLE LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Method Mobile Flow Run codeInstrument Column phase gradient Column T time Method B Waters: Waters:BEH A: 95% 84.2% A for 0.49 min, 0.343 6.2 Acquity C18 (1.7 μm,CH₃COONH₄ to 10.5% A in 40 UPLC ®- 2.1 × 100 mm) 7 mM/5% 2.18 min, heldfor 40 DAD and CH₃CN, B: 1.94 min, back to Quattro CH₃CN 84.2% A in 0.73min, Micro ™ held for 0.73 min.

Hereinafter, “MSD” Mass Selective Detector, “DAD” Diode Array Detector.

TABLE LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Method Flow Run Code InstrumentColumn Mobile phase gradient Column T time Method C Agilent: Agilent:TC- A: CF₃COOH 100% A for 1 min 0.8 10.5 1100/1200- C18 (5 μm, 0.1% inwater, to 40% A in 50 DAD and 2.1 × 50 mm) B: CF₃COOH 4 min, to 15% A inMSD 0.05% in 2.5 min, back to CH₃CN 100% A in 2 min. Method D Agilent:Agilent: TC- A: CF₃COOH 90% A for 0.8 10.5 1100/1200- C18 (5 μm, 0.1% inwater, 0.8 min, to 20% A 50 DAD and 2.1 × 50 mm) B: CF₃COOH in 3.7 min,held MSD 0.05% in for 3 min, back to CH₃CN 90% A in 2 min. Method EAgilent: Waters: A: NH₄OH 100% A for 1 min, 0.8 10.5 1100/1200-XBridge ™ 0.05% in water, to 40% A in 40 DAD and Shield RP18 B: CH₃CN 4min, held for 50 MSD (5 μm, 2.5 min, back to 2.1 × 50 mm) 100% A in 2min.

Pharmacological Examples

MIC Determination for Testing Compounds Against M. tuberculosis.

Test 1

Appropriate solutions of experimental and reference compounds were madein 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosisstrain H37Rv were taken from cultures in logarithmic growth phase. Thesewere first diluted to obtain an optical density of 0.3 at 600 nmwavelength and then diluted 1/100, resulting in an inoculum ofapproximately 5×10 exp5 colony forming units per well. Plates wereincubated at 37° C. in plastic bags to prevent evaporation. After 7days, resazurin was added to all wells. Two days later, fluorescence wasmeasured on a Gemini EM Microplate Reader with 543 excitation and 590 nmemission wavelengths and MIC₅₀ and/or pIC₅₀ values (or the like, e.g.IC₅₀, IC₉₀, pIC₉₀, etc) were (or may be) calculated.

Test 2

Round-bottom, sterile 96-well plastic microtiter plates are filled with100 μl of Middlebrook (1×) 7H9 broth medium. Subsequently, an extra 100μl medium is added to column 2. Stock solutions (200× final testconcentration) of compounds are added in 2 μl volumes to a series ofduplicate wells in column 2 so as to allow evaluation of their effectson bacterial growth. Serial 2-fold dilutions are made directly in themicrotiter plates from column 2 to 11 using a multipipette. Pipette tipsare changed after every 3 dilutions to minimize pipetting errors withhigh hydrophobic compounds. Untreated control samples with (column 1)and without (column 12) inoculum are included in each microtiter plate.Approximately 10000 CFU per well of Mycobacterium tuberculosis (strainH37RV), in a volume of 100 μl in Middlebrook (1×) 7H9 broth medium, isadded to the rows A to H, except column 12. The same volume of brothmedium without inoculum is added to column 12 in row A to H. Thecultures are incubated at 37° C. for 7 days in a humidified atmosphere(incubator with open air valve and continuous ventilation). On day 7 thebacterial growth is checked visually.

The 90% minimal inhibitory concentration (MIC₉₀) is determined as theconcentration with no visual bacterial growth.

Test 3: Time Kill Assays

Bactericidal or bacteriostatic activity of the compounds can bedetermined in a time kill assay using the broth dilution method. In atime kill assay on Mycobacterium tuberculosis (strain H37RV), thestarting inoculum of M. tuberculosis is 10⁶ CFU/ml in Middlebrook (1×)7H9 broth. The antibacterial compounds are used at the concentration of0.1 to 10 times the MIC₉₀. Tubes receiving no antibacterial agentconstitute the culture growth control. The tubes containing themicroorganism and the test compounds are incubated at 37° C. After 0, 1,4, 7, 14 and 21 days of incubation samples are removed for determinationof viable counts by serial dilution (10⁻¹ to 10⁻⁶) in Middlebrook 7H9medium and plating (100 μl) on Middlebrook 7H11 agar. The plates areincubated at 37° C. for 21 days and the number of colonies aredetermined. Killing curves can be constructed by plotting the log₁₀ CFUper ml versus time. A bactericidal effect is commonly defined as 3-log₁₀decrease in number of CFU per ml as compared to untreated inoculum. Thepotential carryover effect of the drugs is removed by serial dilutionsand counting the colonies at highest dilution used for plating.

Test 4 (See Also Test 1 Above; in this Test a Different Strain ofMycobacterium tuberculosis Strain is Employed)

Appropriate solutions of experimental and reference compounds were madein 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosisstrain EH 4.0 (361.269) were taken from cultures in stationary growthphase. These were first diluted to obtain an optical density of 0.3 at600 nm wavelength and then diluted 1/100, resulting in an inoculum ofapproximately 5×10 exp5 colony forming units per well. Plates wereincubated at 37° C. in plastic bags to prevent evaporation. After 7days, resazurin was added to all wells. Two days later, fluorescence wasmeasured on a Gemini EM Microplate Reader with 543 nm excitation and 590nm emission wavelengths and MIC50 and/or pIC50 values (or the like, e.g.IC50, IC90, pIC90, etc) were (or may be) calculated. pIC₅₀ values may berecorded below in μg/mL.

Results

Compounds of the invention/examples, for example when tested in Test 1or Test 2 described above, may typically have an IC₉₀ value from 0.01 to10 μg/ml. Compounds of the invention/examples, for example when testedin Test 1 or Test 2 described above, may typically have a pIC₅₀ from 3to 10 (e.g. from 4.0 to 9.0, such as from 5.0 to 8.0) Compounds of theexamples were tested in Test 1 described above (in section“Pharmacological Examples”) and the following results were obtained:

Biological Data Table Compound No pIC50 pIC50* pIC50** 1 6.87 6.88 6.962 6.17 6.16 6.23 *and **denote repeated (2^(nd) and 3^(rd)) tests in therelevant assay; there may be some experimental deviation observed in theresults

Further Biological Data

Compounds of the examples were tested in Test 4 described above (insection “Pharmacological Examples”) and the following results wereobtained:

Compound No pIC₅₀ Cpd 3 7.3 Cpd 17 7.1 Cpd 7 6.7 Cpd 18 6 Cpd 9 6.85 Cpd19 6.55 Cpd 5 or Cpd 2 6.7 Cpd 16 6.2 Cpd 6 or Cpd 1 7.4 Cpd 15 6.2 Cpd20 6.1 Cpd 21 <4.9 Cpd 22 <4.9 Cpd 23 <4.9 Cpd 4 7.5 Cpd 8 6.8 Cpd 106.9 Cpd 24 8.2 Cpd 25 6.75 Cpd 11 6.45 Cpd 12 <4.9 Cpd 14 6.7 Cpd 13<4.9 Cpd 26 6.4 Cpd 27 6.1

1. A compound of formula (I)

wherein R¹ represents C₁₋₆ alkyl or hydrogen; L¹ represents a linkergroup —C(R^(a))(R^(b))— (or is not present); Het represents aheteroaromatic linker group (which linker group may itself be optionallysubstituted by one or more substituents selected from fluoro, —O—R^(c)and C₁₋₆ alkyl, wherein the latter alkyl moiety is itself optionallysubstituted by one or more fluoro atoms); R^(a), R^(b) and R^(c)independently represent hydrogen or C₁₋₆ alkyl (optionally substitutedby one or more fluoro atoms); X¹ represents —N(R²)(R³); R² and R³: (i)independently represent hydrogen or, preferably, C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from Q¹ and ═O; (ii)independently represent aryl or heteroaryl, each of which is optionallysubstituted by one or more substituents selected from Q²; (iii)independently represent cycloalkyl or heterocycloalkyl, each of which isoptionally substituted by one or more substituents selected from Q³ and═O; or (iv) can be linked together to form: a. a 3- to 8-membered ringoptionally containing one to three heteroatoms (e.g. nitrogen, oxygenand/or sulfur), and which ring is optionally substituted by one or moresubstituents selected from Q⁴ and ═O; b. a “fused” bicyclic ring of thefollowing type:

c. a “spiro” ring of the following type:

Q¹, Q², Q³, Q⁴ and Q⁵ each independently represent one or moresubstituents selected from halo, C₁₋₆ alkyl, —OC₁₋₆ alkyl (which lattertwo alkyl moieties may themselves be optionally substituted by one ormore halo, e.g. fluoro, atoms), aryl and heteroaryl (which latter twoaromatic groups may themselves be optionally substituted by one or moresubstituents selected from halo, C₁₋₆ alkyl and —OC₁₋₆ alkyl, whichlatter two alkyl moieties may themselves be substituted with one or morefluoro atoms); n1 and n2 independently represent 0 or 1; X^(a)represents —C(R^(a1))(R^(b1))_(m)— or —N(R^(c1))—; m represents 1 or 2;each R^(a1) and R^(b1) independently represents fluoro, hydrogen or C₁₋₆alkyl; R^(c1) represents hydrogen or C₁₋₆ alkyl; X^(b) representsC(R^(d)), N, O (in which case L² is not present) or C═O (in which caseL² is also not present); R^(d) represents H, F or —OR^(e) (wherein R^(e)represents H or C₁₋₆ alkyl optionally substituted by one or more fluoroatoms); q¹ represents —X^(c)—(CH₂)_(n1)—X^(d)—; n1 represents 0, 1 or 2;q² represents —X^(e)—(CH₂)_(n2)—X^(f)—; n2 represents 0, 1 or 2, butwherein n1 and n2 do not both represent 0; X^(c) (which is attached toX^(a)) is either not present, or, when X^(a) represents CH, then X mayrepresent —O—, —NH— or —S—; X^(d) is either not present, or, when n1represents 2 or when X^(c) is not present, X^(a) represents C(R^(c)) andn1 represents 1, then X^(d) may also represent —O—, —NH— or —S—; X^(e)and X^(f) independently are either not present, or may independentlyrepresent —O—, —NH— or —S—, provided that the aforementioned heteroatomsare not directly attached to or α to another heteroatom; q³ represents—X^(g)—(CH₂)_(n3)—X^(h)—; q⁴ represents —X^(i)—(CH₂)_(n4)—X^(j)—; n3represents 0, 1 or 2; n4 represents 0, 1 or 2, but wherein n3 and n4 donot both represent 0; X^(g), X^(h), X^(i) and X^(j) independently areeither not present, or may represent —O—, —NH— or —S—, provided that theaforementioned heteroatoms are not directly attached to or a to anotherheteroatom; when X^(b) represents O or C═O, then L² is not present; whenX^(b) represents C(R^(d)) (e.g. CH) or N, then L² may representhydrogen, halo, —OR^(f), —C(O)—R^(g), C₁₋₆ alkyl (optionally substitutedby one or more halo, e.g. fluoro atoms) or an aromatic group (optionallysubstituted by one or more substituents selected from halo, C₁₋₆ alkyl(itself optionally substituted by one or more substituents selected fromfluoro, —CF₃ and/or —SF₅), —OC₁₋₆alkyl (itself optionally substituted byone or more fluoro atoms), —O— phenyl (itself optionally substituted byhalo, C₁₋₆alkyl, C₁₋₆fluoroalkyl and/or —OC₁₋₆alkyl) or —SF₅); R^(f)represents hydrogen, C₁₋₆ alkyl (optionally substituted by one or morefluoro) or an aromatic group (itself optionally substituted by one ormore substituents selected from halo, C₁₋₆alkyl and —OC₁₋₆alkyl, wherethe latter two alkyl moieties may themseleves be optionally substitutedby one or more fluoro atoms); R^(g) represents hydrogen or C₁₋₆alkyl(optionally substituted by one or more substituents selected fromfluoro, or —OC₁₋₃ alkyl, which latter moiety is also optionallysubstituted by one or more fluoro atoms) or an aromatic group(optionally substituted by one or more substituents selected from halo,C₁₋₆ alkyl or —OC₁₋₆alkyl); ring A is a 5-membered aromatic ringcontaining at least one heteroatom (preferably containing at least onenitrogen atom); ring B is a 5- or 6-membered ring, which may be aromaticor non-aromatic, optionally containing one to four heteroatoms(preferably selected from nitrogen, oxygen and sulfur); either ring Aand/or ring B may be optionally substituted by one or more substituentsselected from: halo, C₁₋₆ alkyl (optionally substituted by one or morehalo, e.g. fluoro atoms) and/or —OC₁₋₆alkyl (itself optionallysubstituted by one or more fluoro atoms), or apharmaceutically-acceptable salt thereof.
 2. A compound as claimed inclaim 1, wherein: R¹ represents hydrogen; R^(a) and R^(b) independentlyrepresent hydrogen; and/or L¹ represents —CH₂—.
 3. A compound as claimedin claim 1, wherein when X¹ represents a heteroaromatic linker groupthat is a bicyclic heteroaromatic group linked to L¹ (or the amidomoiety, when L¹ is not present) via a carbocyclic aromatic moiety, soforming e.g.

in which “het” (in the above instance) is a heteroaromatic 5- or6-membered ring.
 4. A compound as claimed in claim 3, wherein the linkergroup is a fused bicyclic ring system comprising a phenyl and/or a 5- or6-membered monocyclic heteroaryl group (for instance forming a 9- or10-membered heteroaromatic group, which consists of two separate ringsfused with each other, in which each ring is 5- or 6-membered so forminga 6,6- or 6,5- or fused bicyclic ring), hence including groups such asthose described below: quinolylene (such as 2-quinolylene or3-quinolylene), e.g.:

quinoxalinyl (such as 2-quinolylene), e.g.:


5. A compound as claimed in claim 1, wherein when X¹ represents—N(R²)(R³), then: (i) R² and R³ independently represent C₁₋₃ alkyl (e.g.methyl or ethyl) optionally substituted by one or more (e.g. one)substituent(s) selected from Q¹; (ii) R² and R³ are linked together toform: a. a 4- to 6-membered ring optionally containing one furtherheteroatom (e.g. so forming a piperidinyl, piperazinyl or azetidinylring), which is optionally (and, in an aspect, preferably) substitutedby Q⁴; b. a fused bicyclic ring in which X^(a) represents —CH₂— andwhich is optionally substituted (e.g. at the X^(a) position) by one ormore (e.g. one) Q⁵ substituent(s); c. a spiro ring system, in whichX^(b) represents CH and L² is present and as defined herein.
 6. Acompound as claimed in claim 1 wherein: ring A is represented asfollows:

ring B is represented as follows:

wherein “SUB” and “Sub” represent one or more possible substituents onthe relevant atom (e.g. carbon or nitrogen atom).
 7. A compound asclaimed in claim 1, wherein the combined ring systems, i.e. Ring A andRing B may be represented as follows:

where “SUB” represents one or more possible substituents on the bicycle(i.e. on ring A and/or on ring B) and “Sub” represents a possibleoptional substituent on the N atom of the bicycle (unsubstituted in thiscontext would mean “NH”).
 8. A compound as claimed in claim 1, wherein:Q¹ represents aryl (e.g. phenyl) optionally substituted by —OC₁₋₃alkyl(itself optionally substituted by one or more fluoro atoms, so forminge.g. a —OCF₃ group); Q⁴ represents aryl (e.g. phenyl) optionallysubstituted by —OC₁₋₃alkyl (itself optionally substituted by one or morefluoro atoms, so forming e.g. a —OCF₃ group); Q⁵ represents halo (e.g.fluoro); X^(c), X^(d), X^(e) and X^(f) are independently not present; n1and n2 independently represent 1; X^(g), X^(h), X^(i) and X^(j) areindependently not present; n3 and n4 independently represent 1; and/orL² represents an aromatic group (e.g. aryl or phenyl) optionallysubstituted by one or more (e.g. one) substituent(s) selected from—OC₁₋₃alkyl (itself optionally substituted by one or more fluoro atoms,so forming e.g. a —OCF₃ group).
 9. A compound of formula (I) as definedin claim 1 but wherein: L¹ represents —CH₂—; Het represents a bicyclicheteroaromatic group linked to L¹ (or the amido moiety, when L¹ is notpresent) via a carbocyclic aromatic moiety, so forming e.g.:

in which “het” (in the above instance) is a heteroaromatic 5- or6-membered ring; when X¹ represents —N(R²)(R³), then: (i) R² and R³independently represent C₁₋₃ alkyl (e.g. methyl or ethyl) optionallysubstituted by one or more (e.g. one) substituent(s) selected from Q¹(but wherein when both R² and R³ represent alkyl, then at least one issubstituted by Q¹ in which Q¹ represents an optionally substituted arylgroup as defined herein); (ii) R² and R³ are linked together to form: a.a 4- to 6-membered ring optionally containing one further heteroatom(e.g. so forming a piperidinyl, piperazinyl or azetidinyl ring), whichis substituted by one or two substituents selected from Q⁴ (in which atleast one Q⁴ substituent is present that represents an optionallysubstituted aryl group as defined herein); b. a fused bicyclic ring inwhich X^(a) represents —CH₂— and which is optionally substituted (e.g.at the X^(a) position) by one or more (e.g. one) Q⁵ substituent(s); c. aspiro ring system, in which X^(b) represents CH and L² is present and asdefined herein; L² represents an aromatic group (e.g. aryl or phenyl)optionally substituted by one or more (e.g. one) substituent(s) e.g.selected from e.g. —OC₁₋₃alkyl (itself optionally substituted by one ormore fluoro atoms, so forming e.g. a —OCF₃ group); ring A and ring Btogether represent a 8 or 9-membered bicyclic ring (ring A is a5-membered ring and ring B may be a 5 or 6-membered ring, in which bothrings are preferably aromatic) containing at least one nitrogen atom(and in a major embodiment, at least one nitrogen atom that is common toboth rings); optional substituents on ring A and ring B are halo, C₁₋₃alkyl and —OC₁₋₃ alkyl; and other integers are as defined herein.
 10. Acompound as claimed in claim 9 wherein: when Q¹ represents aryl, then itis an optionally substituted as defined herein (e.g. by one or moresubstituents selected from —OC₁₋₃alkyl (itself optionally substituted byone or more fluoro atoms, so forming e.g. a —OCF₃ group)); when Q⁴represents aryl, then it is an optionally substituted phenyl as definedherein (e.g. by one or more substituents selected from —OC₁₋₃alkyl(itself optionally substituted by one or more fluoro atoms, so forminge.g. a —OCF₃ group)); when Q⁴ represents a non-aromatic substituent,then it may represent e.g. fluoro; Q⁵ represents halo (e.g. fluoro);X^(c), X^(d), X^(e) and X^(f) are independently not present; n1 and n2independently represent 1; X^(g), X^(h), X^(i) and X^(j) areindependently not present; n3 and n4 independently represent
 1. 11. Acompound as claimed in claim 9 wherein: the X^(b)-containing rings arerepresented as defined herein or more particularly as follows:

(or any one of the above-mentioned representations); and/or the ring Aand ring B bicycles are represented as defined herein or moreparticularly as follows:

(or any one of the above-mentioned representations).
 12. (canceled) 13.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount ofa compound as defined in any one of claim
 9. 14. (canceled) 15.(canceled)
 16. A method of treatment of a bacterial infection, whichmethod comprises administration of a therapeutically effective amount ofa compound according to claim
 1. 17. A combination of (a) a compoundaccording to claim 1, and (b) one or more other anti-tuberculosis agent.18. (canceled)
 19. A process for the preparation of a compound offormula (I) as claimed in claim 1, which process comprises: (i) reactionof a compound of formula (II),

wherein the integers are as defined in claim 1, or a suitable derivativethereof, with a compound of formula (III)

wherein the integers are as defined in claim 1; (ii) coupling of acompound of formula (IV),

wherein the integers are as defined in claim 1, and LG² represents asuitable leaving group, with a compound of formula (V),X¹—H  (V) wherein the integers are as defined in claim 1.